Discovery of\nCHD1 Antagonists for PTEN-Deficient Prostate\nCancer

CHD1 is a chromodomain-helicase DNA-binding protein that\npreferentially\nrecognizes di- and trimethylated lysine 4 on histone H3 (H3K4me2/3).\nGenetic studies have established CHD1 as a synthetic lethal target\nin phosphatase and tensin homologue (PTEN)-deficient cancers. Despite\nthis attractive therapeutic link, no inhibitors or antagonists of\nCHD1 have been reported to date. Herein, we report the discovery of\nUNC10142, a first-in-class small molecule antagonist of the tandem\nchromodomains of CHD1 that binds with an IC<sub>50</sub> of 1.7 ±\n0.2 μM. A cocrystal structure revealed a unique binding mode\nand competition pull-down experiments in cell lysates confirmed endogenous\ntarget engagement. Treatment of PTEN-deficient prostate cancer cells\nwith UNC10142 led to a dose-dependent reduction in viability while\nPTEN-intact prostate cancer cells were unaffected, phenocopying genetic\nloss of CHD1. Overall, this study demonstrates the ligandability of\nthe CHD1 chromodomains and suggests more potent and selective antagonists\ncould translate to compounds of therapeutic value in PTEN-deficient\ncancers.