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PPM1D is a serine/threonine phosphatase recurrently activated in cancer, regulates the DNA damage response (DDR), and suppresses p53. Though PPM1D inhibition impairs tumor growth in cancer models and is the subject of multiple drug discovery efforts, no PPM1D inhibitors with clinical potential have been identified. We screened 600,000 compounds in a displacement assay and generated a hit series with nanomolar activity. We optimized our leads using internally developed assays to interrogate PPM1D, p53, and the DDR and defined important structure-activity relationships. Using an bioluminescent readout of p53 activation, we compared different DDR and p53 modulators and showed that despite having a distinct chemical structure, our lead compound had comparable activity to established PPM1D inhibitors. Our approach yielded multiple allosteric inhibitors of PPM1D, deepened our understanding of PPM1D as a drug target, and is highly amenable to studying other modulators of the DDR and p53.