/ en /news/new-drug-triggers-rapid-cell-death-cancer-models <span class="field field--name-title field--type-string field--label-hidden"><h1>New drug triggers rapid cell death in cancer models</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Karen Zusi-Tran</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-29T11:11:58-04:00" class="datetime">October 29, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>New drug triggers rapid cell death in cancer models</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>BRD-810 inhibits the MCL1 protein and reactivates apoptosis in tumor cells, displaying therapeutic potential in animal models.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Karen Zusi-Tran </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-29T11:11:58-04:00" title="Tuesday, October 29, 2024 - 11:11" class="datetime">October 29, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/nci-vol-2336-150_AML.jpeg?itok=-G4GeifU 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/nci-vol-2336-150_AML.jpeg?itok=-G4GeifU 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/nci-vol-2336-150_AML.jpeg?itok=WN8HdeUZ 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/nci-vol-2336-150_AML.jpeg?itok=RR-LTN2d 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sVD0cixC 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sTYzk9MD 1x" media="all and (max-width: 539px)" type="image/jpeg" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sTYzk9MD" alt="Human cells with acute myelocytic leukemia (AML) in the pericardial fluid." title="Human cells with acute myelocytic leukemia (AML) in the pericardial fluid." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: National Cancer Institute </div> <div class="media-caption__description"> Human cells with acute myelocytic leukemia (AML) in the pericardial fluid. </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous"></div> <div 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class="social-sharing-buttons-button share-email" target="_blank" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#email" /> </svg> </a> </div> </div> <div class="block block-layout-builder block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related groups</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/center-development-therapeutics-cdot">Center for the Development of Therapeutics (CDoT)</a></div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>A team of researchers at ӳ����ý of MIT and Harvard, in a long-term project that has included industry collaborators at Bayer and Trueline Therapeutics, has developed a compound called BRD-810 that holds promise as a therapeutic candidate for cancer. This small molecule reactivates the apoptosis cascade in tumor cells while sparing healthy cells in animal models.&nbsp;</p> <p>Apoptosis, or programmed cell death, is a natural end process for all cells. But many cancers have mechanisms to block this cascade, allowing them to proliferate dangerously. BRD-810 restores the normal apoptotic process by inhibiting a protein called MCL1, which normally protects cells from apoptosis. MCL1 is one of the most highly overexpressed proteins in many cancer types, particularly those that are resistant to standard chemotherapies — making it an attractive drug target.&nbsp;</p> <p>In a study published in <a href="https://www.nature.com/articles/s43018-024-00814-0" target="_blank"><em>Nature Cancer</em></a>, the team showed that their compound binds to MCL1, removing its protective effects and triggering cell death in cancer. Importantly, unlike other MCL1 inhibitors that have raised concerns about cardiovascular side effects in early-stage clinical trials, BRD-810 acts quickly within cancer cells and is eliminated from the body in animal models within a few hours. This rapid clearance minimizes the drug’s potential impact on healthy cells.</p> <p>“BRD-810 is a potent inhibitor with exciting potential as an anticancer agent,” says senior author <a href="/bios/todd-r-golub" target="_blank">Todd Golub</a>, director of the ӳ����ý. “Our team has worked hard to optimize this compound with our collaborators, resulting in promising preclinical data, and we’re eager to develop it further.”</p> <p>Ulrike Rauh, former CEO/CSO of Trueline Therapeutics and current Chief Development Officer at Prosion Therapeutics, is the lead author of the paper.</p> <h2>Reactivating apoptosis</h2> <p>The journey to BRD-810 began more than a decade ago when ӳ����ý researchers, including members of ӳ����ý’s <a href="/center-development-therapeutics-cdot" target="_blank">Center for the Development of Therapeutics</a>, began investigating MCL1 inhibitors in screening tests. The first starting material they identified was too large to be a viable drug, so the team worked with collaborators at Bayer AG to analyze its structure and refine it while maintaining its ability to bind to MCL1. The result was the compound named BRD-810.&nbsp;</p> <p>To assess BRD-810’s effectiveness, the researchers used the <a href="https://www.theprismlab.org/" target="_blank">PRISM</a> platform at ӳ����ý to screen over 700 cell lines representing 32 different cancer lineages. The compound inhibited the growth of a broad range of cancer models, including breast cancer, lung cancer, melanoma, sarcoma, lymphoma, and leukemia.</p> <p>Previous clinical and laboratory studies on other MCL1 inhibitors have suggested that these molecules can impair heart cells, likely because of prolonged exposure to the compounds. So the team turned their attention to optimizing the pharmacokinetic profile of BRD-810 to preserve its ability to kill tumor cells without negatively affecting heart cells.</p> <p>In cell models, BRD-810 effectively killed cancer cells within four hours of administration, and did not impact cardiomyocytes derived from human induced pluripotent stem cells during the same timespan. In collaboration with Trueline Therapeutics, the team fine-tuned this dosing strategy in animal models to maximize anti-cancer activity while minimizing risks. In mouse models, the compound triggered strong tumor regression and did not cause any weight loss (used as a marker for physiological stress). Trueline Therapeutics also tested the compound in a canine model and did not detect any markers of cardiac toxicity.</p> <p>Moving forward, the ӳ����ý team hopes to advance BRD-810 into clinical testing as a potential treatment for a range of cancer types, either as a standalone therapy or in combination with other cancer drugs to enhance their efficacy.</p> <p>“I’m thrilled about the potential of this compound,” said Rauh, who first joined the project while working as a scientist at Bayer. “Developing BRD-810 and witnessing its potential to overcome the challenges associated with MCL1 inhibition has been incredibly rewarding. And this project beautifully illustrates how powerful it is to combine ӳ����ý’s biology expertise and creative approaches to drug discovery with the expertise and capabilities of industry.”</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this research was provided in part by the Robertson Foundation and a National Cancer Institute grant 5R35CA242457.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Rauh U, et al. <a href="https://www.nature.com/articles/s43018-024-00814-0">BRD-810 is a highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models</a>. <em>Nature Cancer</em>. Online August 23, 2024. DOI: 10.1038/s43018-024-00814-0.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/center-development-therapeutics" hreflang="en">Center for the Development of Therapeutics</a></div> <div class="field__item"><a href="/broad-tags/licensing-data-tools-and-technologies" hreflang="en">Licensing data, tools, and technologies</a></div> <div class="field__item"><a href="/broad-tags/cancer" hreflang="en">Cancer</a></div> <div class="field__item"><a href="/broad-tags/drug-discovery-0" hreflang="en">Drug discovery</a></div> </div> </div> </div> </div> </div> Tue, 29 Oct 2024 15:11:58 +0000 kzusi@broadinstitute.org 5557691 at /news/new-protein-complex-structure-reveals-possible-ways-target-key-cancer-pathway <span class="field field--name-title field--type-string field--label-hidden"><h1>New drug triggers rapid cell death in cancer models</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Karen Zusi-Tran</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-29T11:11:58-04:00" class="datetime">October 29, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>New drug triggers rapid cell death in cancer models</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>BRD-810 inhibits the MCL1 protein and reactivates apoptosis in tumor cells, displaying therapeutic potential in animal models.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Karen Zusi-Tran </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-29T11:11:58-04:00" title="Tuesday, October 29, 2024 - 11:11" class="datetime">October 29, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/nci-vol-2336-150_AML.jpeg?itok=-G4GeifU 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/nci-vol-2336-150_AML.jpeg?itok=-G4GeifU 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/nci-vol-2336-150_AML.jpeg?itok=WN8HdeUZ 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/nci-vol-2336-150_AML.jpeg?itok=RR-LTN2d 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sVD0cixC 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sTYzk9MD 1x" media="all and (max-width: 539px)" type="image/jpeg" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sTYzk9MD" alt="Human cells with acute myelocytic leukemia (AML) in the pericardial fluid." title="Human cells with acute myelocytic leukemia (AML) in the pericardial fluid." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: National Cancer Institute </div> <div class="media-caption__description"> Human cells with acute myelocytic leukemia (AML) in the pericardial fluid. </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous"></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/1146/feed&amp;title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#facebook" /> </svg> </a> <a href="https://twitter.com/intent/tweet?text=+/taxonomy/term/1146/feed" target="_blank" title="Share to X" aria-label="Share to X" class="social-sharing-buttons-button share-x" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#x" /> </svg> </a> <a href="mailto:?subject=&amp;body=/taxonomy/term/1146/feed" title="Share to Email" aria-label="Share to Email" class="social-sharing-buttons-button share-email" target="_blank" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#email" /> </svg> </a> </div> </div> <div class="block block-layout-builder block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related groups</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/center-development-therapeutics-cdot">Center for the Development of Therapeutics (CDoT)</a></div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>A team of researchers at ӳ����ý of MIT and Harvard, in a long-term project that has included industry collaborators at Bayer and Trueline Therapeutics, has developed a compound called BRD-810 that holds promise as a therapeutic candidate for cancer. This small molecule reactivates the apoptosis cascade in tumor cells while sparing healthy cells in animal models.&nbsp;</p> <p>Apoptosis, or programmed cell death, is a natural end process for all cells. But many cancers have mechanisms to block this cascade, allowing them to proliferate dangerously. BRD-810 restores the normal apoptotic process by inhibiting a protein called MCL1, which normally protects cells from apoptosis. MCL1 is one of the most highly overexpressed proteins in many cancer types, particularly those that are resistant to standard chemotherapies — making it an attractive drug target.&nbsp;</p> <p>In a study published in <a href="https://www.nature.com/articles/s43018-024-00814-0" target="_blank"><em>Nature Cancer</em></a>, the team showed that their compound binds to MCL1, removing its protective effects and triggering cell death in cancer. Importantly, unlike other MCL1 inhibitors that have raised concerns about cardiovascular side effects in early-stage clinical trials, BRD-810 acts quickly within cancer cells and is eliminated from the body in animal models within a few hours. This rapid clearance minimizes the drug’s potential impact on healthy cells.</p> <p>“BRD-810 is a potent inhibitor with exciting potential as an anticancer agent,” says senior author <a href="/bios/todd-r-golub" target="_blank">Todd Golub</a>, director of the ӳ����ý. “Our team has worked hard to optimize this compound with our collaborators, resulting in promising preclinical data, and we’re eager to develop it further.”</p> <p>Ulrike Rauh, former CEO/CSO of Trueline Therapeutics and current Chief Development Officer at Prosion Therapeutics, is the lead author of the paper.</p> <h2>Reactivating apoptosis</h2> <p>The journey to BRD-810 began more than a decade ago when ӳ����ý researchers, including members of ӳ����ý’s <a href="/center-development-therapeutics-cdot" target="_blank">Center for the Development of Therapeutics</a>, began investigating MCL1 inhibitors in screening tests. The first starting material they identified was too large to be a viable drug, so the team worked with collaborators at Bayer AG to analyze its structure and refine it while maintaining its ability to bind to MCL1. The result was the compound named BRD-810.&nbsp;</p> <p>To assess BRD-810’s effectiveness, the researchers used the <a href="https://www.theprismlab.org/" target="_blank">PRISM</a> platform at ӳ����ý to screen over 700 cell lines representing 32 different cancer lineages. The compound inhibited the growth of a broad range of cancer models, including breast cancer, lung cancer, melanoma, sarcoma, lymphoma, and leukemia.</p> <p>Previous clinical and laboratory studies on other MCL1 inhibitors have suggested that these molecules can impair heart cells, likely because of prolonged exposure to the compounds. So the team turned their attention to optimizing the pharmacokinetic profile of BRD-810 to preserve its ability to kill tumor cells without negatively affecting heart cells.</p> <p>In cell models, BRD-810 effectively killed cancer cells within four hours of administration, and did not impact cardiomyocytes derived from human induced pluripotent stem cells during the same timespan. In collaboration with Trueline Therapeutics, the team fine-tuned this dosing strategy in animal models to maximize anti-cancer activity while minimizing risks. In mouse models, the compound triggered strong tumor regression and did not cause any weight loss (used as a marker for physiological stress). Trueline Therapeutics also tested the compound in a canine model and did not detect any markers of cardiac toxicity.</p> <p>Moving forward, the ӳ����ý team hopes to advance BRD-810 into clinical testing as a potential treatment for a range of cancer types, either as a standalone therapy or in combination with other cancer drugs to enhance their efficacy.</p> <p>“I’m thrilled about the potential of this compound,” said Rauh, who first joined the project while working as a scientist at Bayer. “Developing BRD-810 and witnessing its potential to overcome the challenges associated with MCL1 inhibition has been incredibly rewarding. And this project beautifully illustrates how powerful it is to combine ӳ����ý’s biology expertise and creative approaches to drug discovery with the expertise and capabilities of industry.”</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this research was provided in part by the Robertson Foundation and a National Cancer Institute grant 5R35CA242457.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Rauh U, et al. <a href="https://www.nature.com/articles/s43018-024-00814-0">BRD-810 is a highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models</a>. <em>Nature Cancer</em>. Online August 23, 2024. DOI: 10.1038/s43018-024-00814-0.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/center-development-therapeutics" hreflang="en">Center for the Development of Therapeutics</a></div> <div class="field__item"><a href="/broad-tags/licensing-data-tools-and-technologies" hreflang="en">Licensing data, tools, and technologies</a></div> <div class="field__item"><a href="/broad-tags/cancer" hreflang="en">Cancer</a></div> <div class="field__item"><a href="/broad-tags/drug-discovery-0" hreflang="en">Drug discovery</a></div> </div> </div> </div> </div> </div> Wed, 13 Jul 2022 05:04:00 +0000 aviveros@broadinstitute.org 1145591 at /how-broad-scientists-are-bridging-gap-between-biological-insights-and-new-therapies <span class="field field--name-title field--type-string field--label-hidden"><h1>New drug triggers rapid cell death in cancer models</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Karen Zusi-Tran</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-29T11:11:58-04:00" class="datetime">October 29, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>New drug triggers rapid cell death in cancer models</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>BRD-810 inhibits the MCL1 protein and reactivates apoptosis in tumor cells, displaying therapeutic potential in animal models.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Karen Zusi-Tran </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-29T11:11:58-04:00" title="Tuesday, October 29, 2024 - 11:11" class="datetime">October 29, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/nci-vol-2336-150_AML.jpeg?itok=-G4GeifU 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/nci-vol-2336-150_AML.jpeg?itok=-G4GeifU 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/nci-vol-2336-150_AML.jpeg?itok=WN8HdeUZ 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/nci-vol-2336-150_AML.jpeg?itok=RR-LTN2d 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sVD0cixC 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sTYzk9MD 1x" media="all and (max-width: 539px)" type="image/jpeg" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sTYzk9MD" alt="Human cells with acute myelocytic leukemia (AML) in the pericardial fluid." title="Human cells with acute myelocytic leukemia (AML) in the pericardial fluid." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: National Cancer Institute </div> <div class="media-caption__description"> Human cells with acute myelocytic leukemia (AML) in the pericardial fluid. </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous"></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/1146/feed&amp;title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#facebook" /> </svg> </a> <a href="https://twitter.com/intent/tweet?text=+/taxonomy/term/1146/feed" target="_blank" title="Share to X" aria-label="Share to X" class="social-sharing-buttons-button share-x" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#x" /> </svg> </a> <a href="mailto:?subject=&amp;body=/taxonomy/term/1146/feed" title="Share to Email" aria-label="Share to Email" class="social-sharing-buttons-button share-email" target="_blank" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#email" /> </svg> </a> </div> </div> <div class="block block-layout-builder block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related groups</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/center-development-therapeutics-cdot">Center for the Development of Therapeutics (CDoT)</a></div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>A team of researchers at ӳ����ý of MIT and Harvard, in a long-term project that has included industry collaborators at Bayer and Trueline Therapeutics, has developed a compound called BRD-810 that holds promise as a therapeutic candidate for cancer. This small molecule reactivates the apoptosis cascade in tumor cells while sparing healthy cells in animal models.&nbsp;</p> <p>Apoptosis, or programmed cell death, is a natural end process for all cells. But many cancers have mechanisms to block this cascade, allowing them to proliferate dangerously. BRD-810 restores the normal apoptotic process by inhibiting a protein called MCL1, which normally protects cells from apoptosis. MCL1 is one of the most highly overexpressed proteins in many cancer types, particularly those that are resistant to standard chemotherapies — making it an attractive drug target.&nbsp;</p> <p>In a study published in <a href="https://www.nature.com/articles/s43018-024-00814-0" target="_blank"><em>Nature Cancer</em></a>, the team showed that their compound binds to MCL1, removing its protective effects and triggering cell death in cancer. Importantly, unlike other MCL1 inhibitors that have raised concerns about cardiovascular side effects in early-stage clinical trials, BRD-810 acts quickly within cancer cells and is eliminated from the body in animal models within a few hours. This rapid clearance minimizes the drug’s potential impact on healthy cells.</p> <p>“BRD-810 is a potent inhibitor with exciting potential as an anticancer agent,” says senior author <a href="/bios/todd-r-golub" target="_blank">Todd Golub</a>, director of the ӳ����ý. “Our team has worked hard to optimize this compound with our collaborators, resulting in promising preclinical data, and we’re eager to develop it further.”</p> <p>Ulrike Rauh, former CEO/CSO of Trueline Therapeutics and current Chief Development Officer at Prosion Therapeutics, is the lead author of the paper.</p> <h2>Reactivating apoptosis</h2> <p>The journey to BRD-810 began more than a decade ago when ӳ����ý researchers, including members of ӳ����ý’s <a href="/center-development-therapeutics-cdot" target="_blank">Center for the Development of Therapeutics</a>, began investigating MCL1 inhibitors in screening tests. The first starting material they identified was too large to be a viable drug, so the team worked with collaborators at Bayer AG to analyze its structure and refine it while maintaining its ability to bind to MCL1. The result was the compound named BRD-810.&nbsp;</p> <p>To assess BRD-810’s effectiveness, the researchers used the <a href="https://www.theprismlab.org/" target="_blank">PRISM</a> platform at ӳ����ý to screen over 700 cell lines representing 32 different cancer lineages. The compound inhibited the growth of a broad range of cancer models, including breast cancer, lung cancer, melanoma, sarcoma, lymphoma, and leukemia.</p> <p>Previous clinical and laboratory studies on other MCL1 inhibitors have suggested that these molecules can impair heart cells, likely because of prolonged exposure to the compounds. So the team turned their attention to optimizing the pharmacokinetic profile of BRD-810 to preserve its ability to kill tumor cells without negatively affecting heart cells.</p> <p>In cell models, BRD-810 effectively killed cancer cells within four hours of administration, and did not impact cardiomyocytes derived from human induced pluripotent stem cells during the same timespan. In collaboration with Trueline Therapeutics, the team fine-tuned this dosing strategy in animal models to maximize anti-cancer activity while minimizing risks. In mouse models, the compound triggered strong tumor regression and did not cause any weight loss (used as a marker for physiological stress). Trueline Therapeutics also tested the compound in a canine model and did not detect any markers of cardiac toxicity.</p> <p>Moving forward, the ӳ����ý team hopes to advance BRD-810 into clinical testing as a potential treatment for a range of cancer types, either as a standalone therapy or in combination with other cancer drugs to enhance their efficacy.</p> <p>“I’m thrilled about the potential of this compound,” said Rauh, who first joined the project while working as a scientist at Bayer. “Developing BRD-810 and witnessing its potential to overcome the challenges associated with MCL1 inhibition has been incredibly rewarding. And this project beautifully illustrates how powerful it is to combine ӳ����ý’s biology expertise and creative approaches to drug discovery with the expertise and capabilities of industry.”</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this research was provided in part by the Robertson Foundation and a National Cancer Institute grant 5R35CA242457.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Rauh U, et al. <a href="https://www.nature.com/articles/s43018-024-00814-0">BRD-810 is a highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models</a>. <em>Nature Cancer</em>. Online August 23, 2024. DOI: 10.1038/s43018-024-00814-0.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/center-development-therapeutics" hreflang="en">Center for the Development of Therapeutics</a></div> <div class="field__item"><a href="/broad-tags/licensing-data-tools-and-technologies" hreflang="en">Licensing data, tools, and technologies</a></div> <div class="field__item"><a href="/broad-tags/cancer" hreflang="en">Cancer</a></div> <div class="field__item"><a href="/broad-tags/drug-discovery-0" hreflang="en">Drug discovery</a></div> </div> </div> </div> </div> </div> Wed, 16 Feb 2022 16:16:47 +0000 adicorat 1127161 at /blog/whyiscience-qa-drug-discovery-scientist-discusses-broad-institute%E2%80%99s-unique-role-drug <span class="field field--name-title field--type-string field--label-hidden"><h1>New drug triggers rapid cell death in cancer models</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Karen Zusi-Tran</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-29T11:11:58-04:00" class="datetime">October 29, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>New drug triggers rapid cell death in cancer models</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>BRD-810 inhibits the MCL1 protein and reactivates apoptosis in tumor cells, displaying therapeutic potential in animal models.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Karen Zusi-Tran </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-29T11:11:58-04:00" title="Tuesday, October 29, 2024 - 11:11" class="datetime">October 29, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/nci-vol-2336-150_AML.jpeg?itok=-G4GeifU 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/nci-vol-2336-150_AML.jpeg?itok=-G4GeifU 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/nci-vol-2336-150_AML.jpeg?itok=WN8HdeUZ 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/nci-vol-2336-150_AML.jpeg?itok=RR-LTN2d 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sVD0cixC 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sTYzk9MD 1x" media="all and (max-width: 539px)" type="image/jpeg" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sTYzk9MD" alt="Human cells with acute myelocytic leukemia (AML) in the pericardial fluid." title="Human cells with acute myelocytic leukemia (AML) in the pericardial fluid." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: National Cancer Institute </div> <div class="media-caption__description"> Human cells with acute myelocytic leukemia (AML) in the pericardial fluid. </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div 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href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#x" /> </svg> </a> <a href="mailto:?subject=&amp;body=/taxonomy/term/1146/feed" title="Share to Email" aria-label="Share to Email" class="social-sharing-buttons-button share-email" target="_blank" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#email" /> </svg> </a> </div> </div> <div class="block block-layout-builder block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related groups</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/center-development-therapeutics-cdot">Center for the Development of Therapeutics (CDoT)</a></div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>A team of researchers at ӳ����ý of MIT and Harvard, in a long-term project that has included industry collaborators at Bayer and Trueline Therapeutics, has developed a compound called BRD-810 that holds promise as a therapeutic candidate for cancer. This small molecule reactivates the apoptosis cascade in tumor cells while sparing healthy cells in animal models.&nbsp;</p> <p>Apoptosis, or programmed cell death, is a natural end process for all cells. But many cancers have mechanisms to block this cascade, allowing them to proliferate dangerously. BRD-810 restores the normal apoptotic process by inhibiting a protein called MCL1, which normally protects cells from apoptosis. MCL1 is one of the most highly overexpressed proteins in many cancer types, particularly those that are resistant to standard chemotherapies — making it an attractive drug target.&nbsp;</p> <p>In a study published in <a href="https://www.nature.com/articles/s43018-024-00814-0" target="_blank"><em>Nature Cancer</em></a>, the team showed that their compound binds to MCL1, removing its protective effects and triggering cell death in cancer. Importantly, unlike other MCL1 inhibitors that have raised concerns about cardiovascular side effects in early-stage clinical trials, BRD-810 acts quickly within cancer cells and is eliminated from the body in animal models within a few hours. This rapid clearance minimizes the drug’s potential impact on healthy cells.</p> <p>“BRD-810 is a potent inhibitor with exciting potential as an anticancer agent,” says senior author <a href="/bios/todd-r-golub" target="_blank">Todd Golub</a>, director of the ӳ����ý. “Our team has worked hard to optimize this compound with our collaborators, resulting in promising preclinical data, and we’re eager to develop it further.”</p> <p>Ulrike Rauh, former CEO/CSO of Trueline Therapeutics and current Chief Development Officer at Prosion Therapeutics, is the lead author of the paper.</p> <h2>Reactivating apoptosis</h2> <p>The journey to BRD-810 began more than a decade ago when ӳ����ý researchers, including members of ӳ����ý’s <a href="/center-development-therapeutics-cdot" target="_blank">Center for the Development of Therapeutics</a>, began investigating MCL1 inhibitors in screening tests. The first starting material they identified was too large to be a viable drug, so the team worked with collaborators at Bayer AG to analyze its structure and refine it while maintaining its ability to bind to MCL1. The result was the compound named BRD-810.&nbsp;</p> <p>To assess BRD-810’s effectiveness, the researchers used the <a href="https://www.theprismlab.org/" target="_blank">PRISM</a> platform at ӳ����ý to screen over 700 cell lines representing 32 different cancer lineages. The compound inhibited the growth of a broad range of cancer models, including breast cancer, lung cancer, melanoma, sarcoma, lymphoma, and leukemia.</p> <p>Previous clinical and laboratory studies on other MCL1 inhibitors have suggested that these molecules can impair heart cells, likely because of prolonged exposure to the compounds. So the team turned their attention to optimizing the pharmacokinetic profile of BRD-810 to preserve its ability to kill tumor cells without negatively affecting heart cells.</p> <p>In cell models, BRD-810 effectively killed cancer cells within four hours of administration, and did not impact cardiomyocytes derived from human induced pluripotent stem cells during the same timespan. In collaboration with Trueline Therapeutics, the team fine-tuned this dosing strategy in animal models to maximize anti-cancer activity while minimizing risks. In mouse models, the compound triggered strong tumor regression and did not cause any weight loss (used as a marker for physiological stress). Trueline Therapeutics also tested the compound in a canine model and did not detect any markers of cardiac toxicity.</p> <p>Moving forward, the ӳ����ý team hopes to advance BRD-810 into clinical testing as a potential treatment for a range of cancer types, either as a standalone therapy or in combination with other cancer drugs to enhance their efficacy.</p> <p>“I’m thrilled about the potential of this compound,” said Rauh, who first joined the project while working as a scientist at Bayer. “Developing BRD-810 and witnessing its potential to overcome the challenges associated with MCL1 inhibition has been incredibly rewarding. And this project beautifully illustrates how powerful it is to combine ӳ����ý’s biology expertise and creative approaches to drug discovery with the expertise and capabilities of industry.”</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this research was provided in part by the Robertson Foundation and a National Cancer Institute grant 5R35CA242457.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Rauh U, et al. <a href="https://www.nature.com/articles/s43018-024-00814-0">BRD-810 is a highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models</a>. <em>Nature Cancer</em>. Online August 23, 2024. DOI: 10.1038/s43018-024-00814-0.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/center-development-therapeutics" hreflang="en">Center for the Development of Therapeutics</a></div> <div class="field__item"><a href="/broad-tags/licensing-data-tools-and-technologies" hreflang="en">Licensing data, tools, and technologies</a></div> <div class="field__item"><a href="/broad-tags/cancer" hreflang="en">Cancer</a></div> <div class="field__item"><a href="/broad-tags/drug-discovery-0" hreflang="en">Drug discovery</a></div> </div> </div> </div> </div> </div> Wed, 09 Jun 2021 14:00:00 +0000 adicorat 915461 at /blog/combing-through-old-drugs-find-new-ones-covid-19 <span class="field field--name-title field--type-string field--label-hidden"><h1>New drug triggers rapid cell death in cancer models</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Karen Zusi-Tran</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-29T11:11:58-04:00" class="datetime">October 29, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>New drug triggers rapid cell death in cancer models</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>BRD-810 inhibits the MCL1 protein and reactivates apoptosis in tumor cells, displaying therapeutic potential in animal models.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Karen Zusi-Tran </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-29T11:11:58-04:00" title="Tuesday, October 29, 2024 - 11:11" class="datetime">October 29, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/nci-vol-2336-150_AML.jpeg?itok=-G4GeifU 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/nci-vol-2336-150_AML.jpeg?itok=-G4GeifU 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/nci-vol-2336-150_AML.jpeg?itok=WN8HdeUZ 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/nci-vol-2336-150_AML.jpeg?itok=RR-LTN2d 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sVD0cixC 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sTYzk9MD 1x" media="all and (max-width: 539px)" type="image/jpeg" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sTYzk9MD" alt="Human cells with acute myelocytic leukemia (AML) in the pericardial fluid." title="Human cells with acute myelocytic leukemia (AML) in the pericardial fluid." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: National Cancer Institute </div> <div class="media-caption__description"> Human cells with acute myelocytic leukemia (AML) in the pericardial fluid. </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous"></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/1146/feed&amp;title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#facebook" /> </svg> </a> <a href="https://twitter.com/intent/tweet?text=+/taxonomy/term/1146/feed" target="_blank" title="Share to X" aria-label="Share to X" class="social-sharing-buttons-button share-x" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#x" /> </svg> </a> <a href="mailto:?subject=&amp;body=/taxonomy/term/1146/feed" title="Share to Email" aria-label="Share to Email" class="social-sharing-buttons-button share-email" target="_blank" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#email" /> </svg> </a> </div> </div> <div class="block block-layout-builder block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related groups</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/center-development-therapeutics-cdot">Center for the Development of Therapeutics (CDoT)</a></div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>A team of researchers at ӳ����ý of MIT and Harvard, in a long-term project that has included industry collaborators at Bayer and Trueline Therapeutics, has developed a compound called BRD-810 that holds promise as a therapeutic candidate for cancer. This small molecule reactivates the apoptosis cascade in tumor cells while sparing healthy cells in animal models.&nbsp;</p> <p>Apoptosis, or programmed cell death, is a natural end process for all cells. But many cancers have mechanisms to block this cascade, allowing them to proliferate dangerously. BRD-810 restores the normal apoptotic process by inhibiting a protein called MCL1, which normally protects cells from apoptosis. MCL1 is one of the most highly overexpressed proteins in many cancer types, particularly those that are resistant to standard chemotherapies — making it an attractive drug target.&nbsp;</p> <p>In a study published in <a href="https://www.nature.com/articles/s43018-024-00814-0" target="_blank"><em>Nature Cancer</em></a>, the team showed that their compound binds to MCL1, removing its protective effects and triggering cell death in cancer. Importantly, unlike other MCL1 inhibitors that have raised concerns about cardiovascular side effects in early-stage clinical trials, BRD-810 acts quickly within cancer cells and is eliminated from the body in animal models within a few hours. This rapid clearance minimizes the drug’s potential impact on healthy cells.</p> <p>“BRD-810 is a potent inhibitor with exciting potential as an anticancer agent,” says senior author <a href="/bios/todd-r-golub" target="_blank">Todd Golub</a>, director of the ӳ����ý. “Our team has worked hard to optimize this compound with our collaborators, resulting in promising preclinical data, and we’re eager to develop it further.”</p> <p>Ulrike Rauh, former CEO/CSO of Trueline Therapeutics and current Chief Development Officer at Prosion Therapeutics, is the lead author of the paper.</p> <h2>Reactivating apoptosis</h2> <p>The journey to BRD-810 began more than a decade ago when ӳ����ý researchers, including members of ӳ����ý’s <a href="/center-development-therapeutics-cdot" target="_blank">Center for the Development of Therapeutics</a>, began investigating MCL1 inhibitors in screening tests. The first starting material they identified was too large to be a viable drug, so the team worked with collaborators at Bayer AG to analyze its structure and refine it while maintaining its ability to bind to MCL1. The result was the compound named BRD-810.&nbsp;</p> <p>To assess BRD-810’s effectiveness, the researchers used the <a href="https://www.theprismlab.org/" target="_blank">PRISM</a> platform at ӳ����ý to screen over 700 cell lines representing 32 different cancer lineages. The compound inhibited the growth of a broad range of cancer models, including breast cancer, lung cancer, melanoma, sarcoma, lymphoma, and leukemia.</p> <p>Previous clinical and laboratory studies on other MCL1 inhibitors have suggested that these molecules can impair heart cells, likely because of prolonged exposure to the compounds. So the team turned their attention to optimizing the pharmacokinetic profile of BRD-810 to preserve its ability to kill tumor cells without negatively affecting heart cells.</p> <p>In cell models, BRD-810 effectively killed cancer cells within four hours of administration, and did not impact cardiomyocytes derived from human induced pluripotent stem cells during the same timespan. In collaboration with Trueline Therapeutics, the team fine-tuned this dosing strategy in animal models to maximize anti-cancer activity while minimizing risks. In mouse models, the compound triggered strong tumor regression and did not cause any weight loss (used as a marker for physiological stress). Trueline Therapeutics also tested the compound in a canine model and did not detect any markers of cardiac toxicity.</p> <p>Moving forward, the ӳ����ý team hopes to advance BRD-810 into clinical testing as a potential treatment for a range of cancer types, either as a standalone therapy or in combination with other cancer drugs to enhance their efficacy.</p> <p>“I’m thrilled about the potential of this compound,” said Rauh, who first joined the project while working as a scientist at Bayer. “Developing BRD-810 and witnessing its potential to overcome the challenges associated with MCL1 inhibition has been incredibly rewarding. And this project beautifully illustrates how powerful it is to combine ӳ����ý’s biology expertise and creative approaches to drug discovery with the expertise and capabilities of industry.”</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this research was provided in part by the Robertson Foundation and a National Cancer Institute grant 5R35CA242457.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Rauh U, et al. <a href="https://www.nature.com/articles/s43018-024-00814-0">BRD-810 is a highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models</a>. <em>Nature Cancer</em>. Online August 23, 2024. DOI: 10.1038/s43018-024-00814-0.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/center-development-therapeutics" hreflang="en">Center for the Development of Therapeutics</a></div> <div class="field__item"><a href="/broad-tags/licensing-data-tools-and-technologies" hreflang="en">Licensing data, tools, and technologies</a></div> <div class="field__item"><a href="/broad-tags/cancer" hreflang="en">Cancer</a></div> <div class="field__item"><a href="/broad-tags/drug-discovery-0" hreflang="en">Drug discovery</a></div> </div> </div> </div> </div> </div> Tue, 12 May 2020 13:48:25 +0000 Namrata Sengupta 628861 at /news/marriage-microscopy-and-machine-learning <span class="field field--name-title field--type-string field--label-hidden"><h1>New drug triggers rapid cell death in cancer models</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Karen Zusi-Tran</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-29T11:11:58-04:00" class="datetime">October 29, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>New drug triggers rapid cell death in cancer models</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>BRD-810 inhibits the MCL1 protein and reactivates apoptosis in tumor cells, displaying therapeutic potential in animal models.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Karen Zusi-Tran </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-29T11:11:58-04:00" title="Tuesday, October 29, 2024 - 11:11" class="datetime">October 29, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/nci-vol-2336-150_AML.jpeg?itok=-G4GeifU 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/nci-vol-2336-150_AML.jpeg?itok=-G4GeifU 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/nci-vol-2336-150_AML.jpeg?itok=WN8HdeUZ 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/nci-vol-2336-150_AML.jpeg?itok=RR-LTN2d 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sVD0cixC 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sTYzk9MD 1x" media="all and (max-width: 539px)" type="image/jpeg" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sTYzk9MD" alt="Human cells with acute myelocytic leukemia (AML) in the pericardial fluid." title="Human cells with acute myelocytic leukemia (AML) in the pericardial fluid." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: National Cancer Institute </div> <div class="media-caption__description"> Human cells with acute myelocytic leukemia (AML) in the pericardial fluid. </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous"></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/1146/feed&amp;title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#facebook" /> </svg> </a> <a href="https://twitter.com/intent/tweet?text=+/taxonomy/term/1146/feed" target="_blank" title="Share to X" aria-label="Share to X" class="social-sharing-buttons-button share-x" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use 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class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related groups</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/center-development-therapeutics-cdot">Center for the Development of Therapeutics (CDoT)</a></div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>A team of researchers at ӳ����ý of MIT and Harvard, in a long-term project that has included industry collaborators at Bayer and Trueline Therapeutics, has developed a compound called BRD-810 that holds promise as a therapeutic candidate for cancer. This small molecule reactivates the apoptosis cascade in tumor cells while sparing healthy cells in animal models.&nbsp;</p> <p>Apoptosis, or programmed cell death, is a natural end process for all cells. But many cancers have mechanisms to block this cascade, allowing them to proliferate dangerously. BRD-810 restores the normal apoptotic process by inhibiting a protein called MCL1, which normally protects cells from apoptosis. MCL1 is one of the most highly overexpressed proteins in many cancer types, particularly those that are resistant to standard chemotherapies — making it an attractive drug target.&nbsp;</p> <p>In a study published in <a href="https://www.nature.com/articles/s43018-024-00814-0" target="_blank"><em>Nature Cancer</em></a>, the team showed that their compound binds to MCL1, removing its protective effects and triggering cell death in cancer. Importantly, unlike other MCL1 inhibitors that have raised concerns about cardiovascular side effects in early-stage clinical trials, BRD-810 acts quickly within cancer cells and is eliminated from the body in animal models within a few hours. This rapid clearance minimizes the drug’s potential impact on healthy cells.</p> <p>“BRD-810 is a potent inhibitor with exciting potential as an anticancer agent,” says senior author <a href="/bios/todd-r-golub" target="_blank">Todd Golub</a>, director of the ӳ����ý. “Our team has worked hard to optimize this compound with our collaborators, resulting in promising preclinical data, and we’re eager to develop it further.”</p> <p>Ulrike Rauh, former CEO/CSO of Trueline Therapeutics and current Chief Development Officer at Prosion Therapeutics, is the lead author of the paper.</p> <h2>Reactivating apoptosis</h2> <p>The journey to BRD-810 began more than a decade ago when ӳ����ý researchers, including members of ӳ����ý’s <a href="/center-development-therapeutics-cdot" target="_blank">Center for the Development of Therapeutics</a>, began investigating MCL1 inhibitors in screening tests. The first starting material they identified was too large to be a viable drug, so the team worked with collaborators at Bayer AG to analyze its structure and refine it while maintaining its ability to bind to MCL1. The result was the compound named BRD-810.&nbsp;</p> <p>To assess BRD-810’s effectiveness, the researchers used the <a href="https://www.theprismlab.org/" target="_blank">PRISM</a> platform at ӳ����ý to screen over 700 cell lines representing 32 different cancer lineages. The compound inhibited the growth of a broad range of cancer models, including breast cancer, lung cancer, melanoma, sarcoma, lymphoma, and leukemia.</p> <p>Previous clinical and laboratory studies on other MCL1 inhibitors have suggested that these molecules can impair heart cells, likely because of prolonged exposure to the compounds. So the team turned their attention to optimizing the pharmacokinetic profile of BRD-810 to preserve its ability to kill tumor cells without negatively affecting heart cells.</p> <p>In cell models, BRD-810 effectively killed cancer cells within four hours of administration, and did not impact cardiomyocytes derived from human induced pluripotent stem cells during the same timespan. In collaboration with Trueline Therapeutics, the team fine-tuned this dosing strategy in animal models to maximize anti-cancer activity while minimizing risks. In mouse models, the compound triggered strong tumor regression and did not cause any weight loss (used as a marker for physiological stress). Trueline Therapeutics also tested the compound in a canine model and did not detect any markers of cardiac toxicity.</p> <p>Moving forward, the ӳ����ý team hopes to advance BRD-810 into clinical testing as a potential treatment for a range of cancer types, either as a standalone therapy or in combination with other cancer drugs to enhance their efficacy.</p> <p>“I’m thrilled about the potential of this compound,” said Rauh, who first joined the project while working as a scientist at Bayer. “Developing BRD-810 and witnessing its potential to overcome the challenges associated with MCL1 inhibition has been incredibly rewarding. And this project beautifully illustrates how powerful it is to combine ӳ����ý’s biology expertise and creative approaches to drug discovery with the expertise and capabilities of industry.”</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this research was provided in part by the Robertson Foundation and a National Cancer Institute grant 5R35CA242457.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Rauh U, et al. <a href="https://www.nature.com/articles/s43018-024-00814-0">BRD-810 is a highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models</a>. <em>Nature Cancer</em>. Online August 23, 2024. DOI: 10.1038/s43018-024-00814-0.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/center-development-therapeutics" hreflang="en">Center for the Development of Therapeutics</a></div> <div class="field__item"><a href="/broad-tags/licensing-data-tools-and-technologies" hreflang="en">Licensing data, tools, and technologies</a></div> <div class="field__item"><a href="/broad-tags/cancer" hreflang="en">Cancer</a></div> <div class="field__item"><a href="/broad-tags/drug-discovery-0" hreflang="en">Drug discovery</a></div> </div> </div> </div> </div> </div> Mon, 13 Jan 2020 21:17:17 +0000 Corie Lok 626771 at /news/novo-ventures-and-broad-institute-mit-and-harvard-launch-drug-discovery-%E2%80%9Cgreenhouse%E2%80%9D-drive <span class="field field--name-title field--type-string field--label-hidden"><h1>New drug triggers rapid cell death in cancer models</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Karen Zusi-Tran</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-29T11:11:58-04:00" class="datetime">October 29, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>New drug triggers rapid cell death in cancer models</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>BRD-810 inhibits the MCL1 protein and reactivates apoptosis in tumor cells, displaying therapeutic potential in animal models.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Karen Zusi-Tran </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-29T11:11:58-04:00" title="Tuesday, October 29, 2024 - 11:11" class="datetime">October 29, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/nci-vol-2336-150_AML.jpeg?itok=-G4GeifU 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/nci-vol-2336-150_AML.jpeg?itok=-G4GeifU 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/nci-vol-2336-150_AML.jpeg?itok=WN8HdeUZ 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/nci-vol-2336-150_AML.jpeg?itok=RR-LTN2d 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sVD0cixC 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sTYzk9MD 1x" media="all and (max-width: 539px)" type="image/jpeg" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sTYzk9MD" alt="Human cells with acute myelocytic leukemia (AML) in the pericardial fluid." title="Human cells with acute myelocytic leukemia (AML) in the pericardial fluid." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: National Cancer Institute </div> <div class="media-caption__description"> Human cells with acute myelocytic leukemia (AML) in the pericardial fluid. </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous"></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/1146/feed&amp;title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#facebook" /> </svg> </a> <a href="https://twitter.com/intent/tweet?text=+/taxonomy/term/1146/feed" target="_blank" title="Share to X" aria-label="Share to X" class="social-sharing-buttons-button share-x" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#x" /> </svg> </a> <a href="mailto:?subject=&amp;body=/taxonomy/term/1146/feed" title="Share to Email" aria-label="Share to Email" class="social-sharing-buttons-button share-email" target="_blank" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#email" /> </svg> </a> </div> </div> <div class="block block-layout-builder block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related groups</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/center-development-therapeutics-cdot">Center for the Development of Therapeutics (CDoT)</a></div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>A team of researchers at ӳ����ý of MIT and Harvard, in a long-term project that has included industry collaborators at Bayer and Trueline Therapeutics, has developed a compound called BRD-810 that holds promise as a therapeutic candidate for cancer. This small molecule reactivates the apoptosis cascade in tumor cells while sparing healthy cells in animal models.&nbsp;</p> <p>Apoptosis, or programmed cell death, is a natural end process for all cells. But many cancers have mechanisms to block this cascade, allowing them to proliferate dangerously. BRD-810 restores the normal apoptotic process by inhibiting a protein called MCL1, which normally protects cells from apoptosis. MCL1 is one of the most highly overexpressed proteins in many cancer types, particularly those that are resistant to standard chemotherapies — making it an attractive drug target.&nbsp;</p> <p>In a study published in <a href="https://www.nature.com/articles/s43018-024-00814-0" target="_blank"><em>Nature Cancer</em></a>, the team showed that their compound binds to MCL1, removing its protective effects and triggering cell death in cancer. Importantly, unlike other MCL1 inhibitors that have raised concerns about cardiovascular side effects in early-stage clinical trials, BRD-810 acts quickly within cancer cells and is eliminated from the body in animal models within a few hours. This rapid clearance minimizes the drug’s potential impact on healthy cells.</p> <p>“BRD-810 is a potent inhibitor with exciting potential as an anticancer agent,” says senior author <a href="/bios/todd-r-golub" target="_blank">Todd Golub</a>, director of the ӳ����ý. “Our team has worked hard to optimize this compound with our collaborators, resulting in promising preclinical data, and we’re eager to develop it further.”</p> <p>Ulrike Rauh, former CEO/CSO of Trueline Therapeutics and current Chief Development Officer at Prosion Therapeutics, is the lead author of the paper.</p> <h2>Reactivating apoptosis</h2> <p>The journey to BRD-810 began more than a decade ago when ӳ����ý researchers, including members of ӳ����ý’s <a href="/center-development-therapeutics-cdot" target="_blank">Center for the Development of Therapeutics</a>, began investigating MCL1 inhibitors in screening tests. The first starting material they identified was too large to be a viable drug, so the team worked with collaborators at Bayer AG to analyze its structure and refine it while maintaining its ability to bind to MCL1. The result was the compound named BRD-810.&nbsp;</p> <p>To assess BRD-810’s effectiveness, the researchers used the <a href="https://www.theprismlab.org/" target="_blank">PRISM</a> platform at ӳ����ý to screen over 700 cell lines representing 32 different cancer lineages. The compound inhibited the growth of a broad range of cancer models, including breast cancer, lung cancer, melanoma, sarcoma, lymphoma, and leukemia.</p> <p>Previous clinical and laboratory studies on other MCL1 inhibitors have suggested that these molecules can impair heart cells, likely because of prolonged exposure to the compounds. So the team turned their attention to optimizing the pharmacokinetic profile of BRD-810 to preserve its ability to kill tumor cells without negatively affecting heart cells.</p> <p>In cell models, BRD-810 effectively killed cancer cells within four hours of administration, and did not impact cardiomyocytes derived from human induced pluripotent stem cells during the same timespan. In collaboration with Trueline Therapeutics, the team fine-tuned this dosing strategy in animal models to maximize anti-cancer activity while minimizing risks. In mouse models, the compound triggered strong tumor regression and did not cause any weight loss (used as a marker for physiological stress). Trueline Therapeutics also tested the compound in a canine model and did not detect any markers of cardiac toxicity.</p> <p>Moving forward, the ӳ����ý team hopes to advance BRD-810 into clinical testing as a potential treatment for a range of cancer types, either as a standalone therapy or in combination with other cancer drugs to enhance their efficacy.</p> <p>“I’m thrilled about the potential of this compound,” said Rauh, who first joined the project while working as a scientist at Bayer. “Developing BRD-810 and witnessing its potential to overcome the challenges associated with MCL1 inhibition has been incredibly rewarding. And this project beautifully illustrates how powerful it is to combine ӳ����ý’s biology expertise and creative approaches to drug discovery with the expertise and capabilities of industry.”</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this research was provided in part by the Robertson Foundation and a National Cancer Institute grant 5R35CA242457.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Rauh U, et al. <a href="https://www.nature.com/articles/s43018-024-00814-0">BRD-810 is a highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models</a>. <em>Nature Cancer</em>. Online August 23, 2024. DOI: 10.1038/s43018-024-00814-0.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/center-development-therapeutics" hreflang="en">Center for the Development of Therapeutics</a></div> <div class="field__item"><a href="/broad-tags/licensing-data-tools-and-technologies" hreflang="en">Licensing data, tools, and technologies</a></div> <div class="field__item"><a href="/broad-tags/cancer" hreflang="en">Cancer</a></div> <div class="field__item"><a href="/broad-tags/drug-discovery-0" hreflang="en">Drug discovery</a></div> </div> </div> </div> </div> </div> Tue, 19 Nov 2019 12:00:53 +0000 kzusi@broadinstitute.org 625191 at /news/molecular-traffic-jam-may-underlie-rare-kidney-disease-and-several-other-protein-misfolding <span class="field field--name-title field--type-string field--label-hidden"><h1>New drug triggers rapid cell death in cancer models</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Karen Zusi-Tran</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-29T11:11:58-04:00" class="datetime">October 29, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>New drug triggers rapid cell death in cancer models</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>BRD-810 inhibits the MCL1 protein and reactivates apoptosis in tumor cells, displaying therapeutic potential in animal models.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Karen Zusi-Tran </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-29T11:11:58-04:00" title="Tuesday, October 29, 2024 - 11:11" class="datetime">October 29, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/nci-vol-2336-150_AML.jpeg?itok=-G4GeifU 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/nci-vol-2336-150_AML.jpeg?itok=-G4GeifU 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/nci-vol-2336-150_AML.jpeg?itok=WN8HdeUZ 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/nci-vol-2336-150_AML.jpeg?itok=RR-LTN2d 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sVD0cixC 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sTYzk9MD 1x" media="all and (max-width: 539px)" type="image/jpeg" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sTYzk9MD" alt="Human cells with acute myelocytic leukemia (AML) in the pericardial fluid." title="Human cells with acute myelocytic leukemia (AML) in the pericardial fluid." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: National Cancer Institute </div> <div class="media-caption__description"> Human cells with acute myelocytic leukemia (AML) in the pericardial fluid. </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div 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class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related groups</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/center-development-therapeutics-cdot">Center for the Development of Therapeutics (CDoT)</a></div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>A team of researchers at ӳ����ý of MIT and Harvard, in a long-term project that has included industry collaborators at Bayer and Trueline Therapeutics, has developed a compound called BRD-810 that holds promise as a therapeutic candidate for cancer. This small molecule reactivates the apoptosis cascade in tumor cells while sparing healthy cells in animal models.&nbsp;</p> <p>Apoptosis, or programmed cell death, is a natural end process for all cells. But many cancers have mechanisms to block this cascade, allowing them to proliferate dangerously. BRD-810 restores the normal apoptotic process by inhibiting a protein called MCL1, which normally protects cells from apoptosis. MCL1 is one of the most highly overexpressed proteins in many cancer types, particularly those that are resistant to standard chemotherapies — making it an attractive drug target.&nbsp;</p> <p>In a study published in <a href="https://www.nature.com/articles/s43018-024-00814-0" target="_blank"><em>Nature Cancer</em></a>, the team showed that their compound binds to MCL1, removing its protective effects and triggering cell death in cancer. Importantly, unlike other MCL1 inhibitors that have raised concerns about cardiovascular side effects in early-stage clinical trials, BRD-810 acts quickly within cancer cells and is eliminated from the body in animal models within a few hours. This rapid clearance minimizes the drug’s potential impact on healthy cells.</p> <p>“BRD-810 is a potent inhibitor with exciting potential as an anticancer agent,” says senior author <a href="/bios/todd-r-golub" target="_blank">Todd Golub</a>, director of the ӳ����ý. “Our team has worked hard to optimize this compound with our collaborators, resulting in promising preclinical data, and we’re eager to develop it further.”</p> <p>Ulrike Rauh, former CEO/CSO of Trueline Therapeutics and current Chief Development Officer at Prosion Therapeutics, is the lead author of the paper.</p> <h2>Reactivating apoptosis</h2> <p>The journey to BRD-810 began more than a decade ago when ӳ����ý researchers, including members of ӳ����ý’s <a href="/center-development-therapeutics-cdot" target="_blank">Center for the Development of Therapeutics</a>, began investigating MCL1 inhibitors in screening tests. The first starting material they identified was too large to be a viable drug, so the team worked with collaborators at Bayer AG to analyze its structure and refine it while maintaining its ability to bind to MCL1. The result was the compound named BRD-810.&nbsp;</p> <p>To assess BRD-810’s effectiveness, the researchers used the <a href="https://www.theprismlab.org/" target="_blank">PRISM</a> platform at ӳ����ý to screen over 700 cell lines representing 32 different cancer lineages. The compound inhibited the growth of a broad range of cancer models, including breast cancer, lung cancer, melanoma, sarcoma, lymphoma, and leukemia.</p> <p>Previous clinical and laboratory studies on other MCL1 inhibitors have suggested that these molecules can impair heart cells, likely because of prolonged exposure to the compounds. So the team turned their attention to optimizing the pharmacokinetic profile of BRD-810 to preserve its ability to kill tumor cells without negatively affecting heart cells.</p> <p>In cell models, BRD-810 effectively killed cancer cells within four hours of administration, and did not impact cardiomyocytes derived from human induced pluripotent stem cells during the same timespan. In collaboration with Trueline Therapeutics, the team fine-tuned this dosing strategy in animal models to maximize anti-cancer activity while minimizing risks. In mouse models, the compound triggered strong tumor regression and did not cause any weight loss (used as a marker for physiological stress). Trueline Therapeutics also tested the compound in a canine model and did not detect any markers of cardiac toxicity.</p> <p>Moving forward, the ӳ����ý team hopes to advance BRD-810 into clinical testing as a potential treatment for a range of cancer types, either as a standalone therapy or in combination with other cancer drugs to enhance their efficacy.</p> <p>“I’m thrilled about the potential of this compound,” said Rauh, who first joined the project while working as a scientist at Bayer. “Developing BRD-810 and witnessing its potential to overcome the challenges associated with MCL1 inhibition has been incredibly rewarding. And this project beautifully illustrates how powerful it is to combine ӳ����ý’s biology expertise and creative approaches to drug discovery with the expertise and capabilities of industry.”</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this research was provided in part by the Robertson Foundation and a National Cancer Institute grant 5R35CA242457.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Rauh U, et al. <a href="https://www.nature.com/articles/s43018-024-00814-0">BRD-810 is a highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models</a>. <em>Nature Cancer</em>. Online August 23, 2024. DOI: 10.1038/s43018-024-00814-0.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/center-development-therapeutics" hreflang="en">Center for the Development of Therapeutics</a></div> <div class="field__item"><a href="/broad-tags/licensing-data-tools-and-technologies" hreflang="en">Licensing data, tools, and technologies</a></div> <div class="field__item"><a href="/broad-tags/cancer" hreflang="en">Cancer</a></div> <div class="field__item"><a href="/broad-tags/drug-discovery-0" hreflang="en">Drug discovery</a></div> </div> </div> </div> </div> </div> Thu, 25 Jul 2019 15:00:54 +0000 tulrich@broadinstitute.org 571761 at /blog/whyiscience-qa-donald-raymond-solves-structures-proteins-and-supports-development-better-therapeutics <span class="field field--name-title field--type-string field--label-hidden"><h1>New drug triggers rapid cell death in cancer models</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Karen Zusi-Tran</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-29T11:11:58-04:00" class="datetime">October 29, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>New drug triggers rapid cell death in cancer models</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>BRD-810 inhibits the MCL1 protein and reactivates apoptosis in tumor cells, displaying therapeutic potential in animal models.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Karen Zusi-Tran </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-29T11:11:58-04:00" title="Tuesday, October 29, 2024 - 11:11" class="datetime">October 29, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/nci-vol-2336-150_AML.jpeg?itok=-G4GeifU 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/nci-vol-2336-150_AML.jpeg?itok=-G4GeifU 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/nci-vol-2336-150_AML.jpeg?itok=WN8HdeUZ 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/nci-vol-2336-150_AML.jpeg?itok=RR-LTN2d 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sVD0cixC 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sTYzk9MD 1x" media="all and (max-width: 539px)" type="image/jpeg" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sTYzk9MD" alt="Human cells with acute myelocytic leukemia (AML) in the pericardial fluid." title="Human cells with acute myelocytic leukemia (AML) in the pericardial fluid." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: National Cancer Institute </div> <div class="media-caption__description"> Human cells with acute myelocytic leukemia (AML) in the pericardial fluid. </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div 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href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#x" /> </svg> </a> <a href="mailto:?subject=&amp;body=/taxonomy/term/1146/feed" title="Share to Email" aria-label="Share to Email" class="social-sharing-buttons-button share-email" target="_blank" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#email" /> </svg> </a> </div> </div> <div class="block block-layout-builder block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related groups</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/center-development-therapeutics-cdot">Center for the Development of Therapeutics (CDoT)</a></div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>A team of researchers at ӳ����ý of MIT and Harvard, in a long-term project that has included industry collaborators at Bayer and Trueline Therapeutics, has developed a compound called BRD-810 that holds promise as a therapeutic candidate for cancer. This small molecule reactivates the apoptosis cascade in tumor cells while sparing healthy cells in animal models.&nbsp;</p> <p>Apoptosis, or programmed cell death, is a natural end process for all cells. But many cancers have mechanisms to block this cascade, allowing them to proliferate dangerously. BRD-810 restores the normal apoptotic process by inhibiting a protein called MCL1, which normally protects cells from apoptosis. MCL1 is one of the most highly overexpressed proteins in many cancer types, particularly those that are resistant to standard chemotherapies — making it an attractive drug target.&nbsp;</p> <p>In a study published in <a href="https://www.nature.com/articles/s43018-024-00814-0" target="_blank"><em>Nature Cancer</em></a>, the team showed that their compound binds to MCL1, removing its protective effects and triggering cell death in cancer. Importantly, unlike other MCL1 inhibitors that have raised concerns about cardiovascular side effects in early-stage clinical trials, BRD-810 acts quickly within cancer cells and is eliminated from the body in animal models within a few hours. This rapid clearance minimizes the drug’s potential impact on healthy cells.</p> <p>“BRD-810 is a potent inhibitor with exciting potential as an anticancer agent,” says senior author <a href="/bios/todd-r-golub" target="_blank">Todd Golub</a>, director of the ӳ����ý. “Our team has worked hard to optimize this compound with our collaborators, resulting in promising preclinical data, and we’re eager to develop it further.”</p> <p>Ulrike Rauh, former CEO/CSO of Trueline Therapeutics and current Chief Development Officer at Prosion Therapeutics, is the lead author of the paper.</p> <h2>Reactivating apoptosis</h2> <p>The journey to BRD-810 began more than a decade ago when ӳ����ý researchers, including members of ӳ����ý’s <a href="/center-development-therapeutics-cdot" target="_blank">Center for the Development of Therapeutics</a>, began investigating MCL1 inhibitors in screening tests. The first starting material they identified was too large to be a viable drug, so the team worked with collaborators at Bayer AG to analyze its structure and refine it while maintaining its ability to bind to MCL1. The result was the compound named BRD-810.&nbsp;</p> <p>To assess BRD-810’s effectiveness, the researchers used the <a href="https://www.theprismlab.org/" target="_blank">PRISM</a> platform at ӳ����ý to screen over 700 cell lines representing 32 different cancer lineages. The compound inhibited the growth of a broad range of cancer models, including breast cancer, lung cancer, melanoma, sarcoma, lymphoma, and leukemia.</p> <p>Previous clinical and laboratory studies on other MCL1 inhibitors have suggested that these molecules can impair heart cells, likely because of prolonged exposure to the compounds. So the team turned their attention to optimizing the pharmacokinetic profile of BRD-810 to preserve its ability to kill tumor cells without negatively affecting heart cells.</p> <p>In cell models, BRD-810 effectively killed cancer cells within four hours of administration, and did not impact cardiomyocytes derived from human induced pluripotent stem cells during the same timespan. In collaboration with Trueline Therapeutics, the team fine-tuned this dosing strategy in animal models to maximize anti-cancer activity while minimizing risks. In mouse models, the compound triggered strong tumor regression and did not cause any weight loss (used as a marker for physiological stress). Trueline Therapeutics also tested the compound in a canine model and did not detect any markers of cardiac toxicity.</p> <p>Moving forward, the ӳ����ý team hopes to advance BRD-810 into clinical testing as a potential treatment for a range of cancer types, either as a standalone therapy or in combination with other cancer drugs to enhance their efficacy.</p> <p>“I’m thrilled about the potential of this compound,” said Rauh, who first joined the project while working as a scientist at Bayer. “Developing BRD-810 and witnessing its potential to overcome the challenges associated with MCL1 inhibition has been incredibly rewarding. And this project beautifully illustrates how powerful it is to combine ӳ����ý’s biology expertise and creative approaches to drug discovery with the expertise and capabilities of industry.”</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this research was provided in part by the Robertson Foundation and a National Cancer Institute grant 5R35CA242457.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Rauh U, et al. <a href="https://www.nature.com/articles/s43018-024-00814-0">BRD-810 is a highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models</a>. <em>Nature Cancer</em>. Online August 23, 2024. DOI: 10.1038/s43018-024-00814-0.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/center-development-therapeutics" hreflang="en">Center for the Development of Therapeutics</a></div> <div class="field__item"><a href="/broad-tags/licensing-data-tools-and-technologies" hreflang="en">Licensing data, tools, and technologies</a></div> <div class="field__item"><a href="/broad-tags/cancer" hreflang="en">Cancer</a></div> <div class="field__item"><a href="/broad-tags/drug-discovery-0" hreflang="en">Drug discovery</a></div> </div> </div> </div> </div> </div> Tue, 25 Jun 2019 04:00:00 +0000 Abbey Bigler 552071 at /blog/chemist-compound-and-path-bench-bedside <span class="field field--name-title field--type-string field--label-hidden"><h1>New drug triggers rapid cell death in cancer models</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Karen Zusi-Tran</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-29T11:11:58-04:00" class="datetime">October 29, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>New drug triggers rapid cell death in cancer models</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>BRD-810 inhibits the MCL1 protein and reactivates apoptosis in tumor cells, displaying therapeutic potential in animal models.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Karen Zusi-Tran </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-29T11:11:58-04:00" title="Tuesday, October 29, 2024 - 11:11" class="datetime">October 29, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/nci-vol-2336-150_AML.jpeg?itok=-G4GeifU 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/nci-vol-2336-150_AML.jpeg?itok=-G4GeifU 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/nci-vol-2336-150_AML.jpeg?itok=WN8HdeUZ 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/nci-vol-2336-150_AML.jpeg?itok=RR-LTN2d 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sVD0cixC 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sTYzk9MD 1x" media="all and (max-width: 539px)" type="image/jpeg" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/nci-vol-2336-150_AML.jpeg?itok=sTYzk9MD" alt="Human cells with acute myelocytic leukemia (AML) in the pericardial fluid." title="Human cells with acute myelocytic leukemia (AML) in the pericardial fluid." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: National Cancer Institute </div> <div class="media-caption__description"> Human cells with acute myelocytic leukemia (AML) in the pericardial fluid. </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" 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href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#x" /> </svg> </a> <a href="mailto:?subject=&amp;body=/taxonomy/term/1146/feed" title="Share to Email" aria-label="Share to Email" class="social-sharing-buttons-button share-email" target="_blank" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#email" /> </svg> </a> </div> </div> <div class="block block-layout-builder block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related groups</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/center-development-therapeutics-cdot">Center for the Development of Therapeutics (CDoT)</a></div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>A team of researchers at ӳ����ý of MIT and Harvard, in a long-term project that has included industry collaborators at Bayer and Trueline Therapeutics, has developed a compound called BRD-810 that holds promise as a therapeutic candidate for cancer. This small molecule reactivates the apoptosis cascade in tumor cells while sparing healthy cells in animal models.&nbsp;</p> <p>Apoptosis, or programmed cell death, is a natural end process for all cells. But many cancers have mechanisms to block this cascade, allowing them to proliferate dangerously. BRD-810 restores the normal apoptotic process by inhibiting a protein called MCL1, which normally protects cells from apoptosis. MCL1 is one of the most highly overexpressed proteins in many cancer types, particularly those that are resistant to standard chemotherapies — making it an attractive drug target.&nbsp;</p> <p>In a study published in <a href="https://www.nature.com/articles/s43018-024-00814-0" target="_blank"><em>Nature Cancer</em></a>, the team showed that their compound binds to MCL1, removing its protective effects and triggering cell death in cancer. Importantly, unlike other MCL1 inhibitors that have raised concerns about cardiovascular side effects in early-stage clinical trials, BRD-810 acts quickly within cancer cells and is eliminated from the body in animal models within a few hours. This rapid clearance minimizes the drug’s potential impact on healthy cells.</p> <p>“BRD-810 is a potent inhibitor with exciting potential as an anticancer agent,” says senior author <a href="/bios/todd-r-golub" target="_blank">Todd Golub</a>, director of the ӳ����ý. “Our team has worked hard to optimize this compound with our collaborators, resulting in promising preclinical data, and we’re eager to develop it further.”</p> <p>Ulrike Rauh, former CEO/CSO of Trueline Therapeutics and current Chief Development Officer at Prosion Therapeutics, is the lead author of the paper.</p> <h2>Reactivating apoptosis</h2> <p>The journey to BRD-810 began more than a decade ago when ӳ����ý researchers, including members of ӳ����ý’s <a href="/center-development-therapeutics-cdot" target="_blank">Center for the Development of Therapeutics</a>, began investigating MCL1 inhibitors in screening tests. The first starting material they identified was too large to be a viable drug, so the team worked with collaborators at Bayer AG to analyze its structure and refine it while maintaining its ability to bind to MCL1. The result was the compound named BRD-810.&nbsp;</p> <p>To assess BRD-810’s effectiveness, the researchers used the <a href="https://www.theprismlab.org/" target="_blank">PRISM</a> platform at ӳ����ý to screen over 700 cell lines representing 32 different cancer lineages. The compound inhibited the growth of a broad range of cancer models, including breast cancer, lung cancer, melanoma, sarcoma, lymphoma, and leukemia.</p> <p>Previous clinical and laboratory studies on other MCL1 inhibitors have suggested that these molecules can impair heart cells, likely because of prolonged exposure to the compounds. So the team turned their attention to optimizing the pharmacokinetic profile of BRD-810 to preserve its ability to kill tumor cells without negatively affecting heart cells.</p> <p>In cell models, BRD-810 effectively killed cancer cells within four hours of administration, and did not impact cardiomyocytes derived from human induced pluripotent stem cells during the same timespan. In collaboration with Trueline Therapeutics, the team fine-tuned this dosing strategy in animal models to maximize anti-cancer activity while minimizing risks. In mouse models, the compound triggered strong tumor regression and did not cause any weight loss (used as a marker for physiological stress). Trueline Therapeutics also tested the compound in a canine model and did not detect any markers of cardiac toxicity.</p> <p>Moving forward, the ӳ����ý team hopes to advance BRD-810 into clinical testing as a potential treatment for a range of cancer types, either as a standalone therapy or in combination with other cancer drugs to enhance their efficacy.</p> <p>“I’m thrilled about the potential of this compound,” said Rauh, who first joined the project while working as a scientist at Bayer. “Developing BRD-810 and witnessing its potential to overcome the challenges associated with MCL1 inhibition has been incredibly rewarding. And this project beautifully illustrates how powerful it is to combine ӳ����ý’s biology expertise and creative approaches to drug discovery with the expertise and capabilities of industry.”</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this research was provided in part by the Robertson Foundation and a National Cancer Institute grant 5R35CA242457.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Rauh U, et al. <a href="https://www.nature.com/articles/s43018-024-00814-0">BRD-810 is a highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models</a>. <em>Nature Cancer</em>. Online August 23, 2024. DOI: 10.1038/s43018-024-00814-0.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/center-development-therapeutics" hreflang="en">Center for the Development of Therapeutics</a></div> <div class="field__item"><a href="/broad-tags/licensing-data-tools-and-technologies" hreflang="en">Licensing data, tools, and technologies</a></div> <div class="field__item"><a href="/broad-tags/cancer" hreflang="en">Cancer</a></div> <div class="field__item"><a href="/broad-tags/drug-discovery-0" hreflang="en">Drug discovery</a></div> </div> </div> </div> </div> </div> Tue, 16 Apr 2019 15:50:23 +0000 tulrich@broadinstitute.org 500746 at