New drug triggers rapid cell death in cancer models

kzusi@broadinstitute.org — Tue, 29 Oct 2024 15:11:58 +0000

New drug triggers rapid cell death in cancer models

By Karen Zusi-Tran October 29, 2024

New drug triggers rapid cell death in cancer models

BRD-810 inhibits the MCL1 protein and reactivates apoptosis in tumor cells, displaying therapeutic potential in animal models.

By Karen Zusi-Tran

October 29, 2024

Credit: National Cancer Institute

Human cells with acute myelocytic leukemia (AML) in the pericardial fluid.

A team of researchers at 映画传媒 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.

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 鈥� making it an attractive drug target.

In a study published in Nature Cancer, 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鈥檚 potential impact on healthy cells.

鈥淏RD-810 is a potent inhibitor with exciting potential as an anticancer agent,鈥� says senior author Todd Golub, director of the 映画传媒. 鈥淥ur team has worked hard to optimize this compound with our collaborators, resulting in promising preclinical data, and we鈥檙e eager to develop it further.鈥�

Ulrike Rauh, former CEO/CSO of Trueline Therapeutics and current Chief Development Officer at Prosion Therapeutics, is the lead author of the paper.

Reactivating apoptosis

The journey to BRD-810 began more than a decade ago when 映画传媒 researchers, including members of 映画传媒鈥檚 Center for the Development of Therapeutics, 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.

To assess BRD-810鈥檚 effectiveness, the researchers used the PRISM platform at 映画传媒 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.

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.

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.

Moving forward, the 映画传媒 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.

鈥淚鈥檓 thrilled about the potential of this compound,鈥� said Rauh, who first joined the project while working as a scientist at Bayer. 鈥淒eveloping 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 映画传媒鈥檚 biology expertise and creative approaches to drug discovery with the expertise and capabilities of industry.鈥�

Funding

Support for this research was provided in part by the Robertson Foundation and a National Cancer Institute grant 5R35CA242457.

Paper cited

Rauh U, et al. BRD-810 is a highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models. Nature Cancer. Online August 23, 2024. DOI: 10.1038/s43018-024-00814-0.

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Center for the Development of Therapeutics