CHD1 is a chromodomain-helicase DNA-binding protein that preferentially recognizes di- and trimethylated lysine 4 on histone H3 (H3K4me2/3). Genetic studies have established CHD1 as a synthetic lethal target in phosphatase and tensin homologue (PTEN)-deficient cancers. Despite this attractive therapeutic link, no inhibitors or antagonists of CHD1 have been reported to date. Herein, we report the discovery of UNC10142, a first-in-class small molecule antagonist of the tandem chromodomains of CHD1 that binds with an IC₅₀ of 1.7 ± 0.2 μM. A cocrystal structure revealed a unique binding mode and competition pull-down experiments in cell lysates confirmed endogenous target engagement. Treatment of PTEN-deficient prostate cancer cells with UNC10142 led to a dose-dependent reduction in viability while PTEN-intact prostate cancer cells were unaffected, phenocopying genetic loss of CHD1. Overall, this study demonstrates the ligandability of the CHD1 chromodomains and suggests more potent and selective antagonists could translate to compounds of therapeutic value in PTEN-deficient cancers.

中文翻译：

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发现 CHD1 拮抗剂治疗 PTEN 缺陷型前列腺癌


CHD1 是一种染色质域-解旋酶 DNA 结合蛋白，优先识别组蛋白 H3 （H3K4me2/3） 上的二甲基化和三甲基化赖氨酸 4。遗传学研究已确定 CHD1 是磷酸酶和张力蛋白同源物 （PTEN） 缺陷型癌症的合成致死靶标。尽管存在这种有吸引力的治疗联系，但迄今为止尚未报道 CHD1 的抑制剂或拮抗剂。在此，我们报道了 UNC10142 的发现， 是 CHD1 串联染色质结构域的一流小分子拮抗剂，其结合 IC₅₀ 为 1.7 ± 0.2 μM。共晶结构揭示了独特的结合模式，细胞裂解物中的竞争性 pull-down 实验证实了内源性靶标结合。用 UNC10142 治疗 PTEN 缺陷的前列腺癌细胞导致活力呈剂量依赖性降低，而 PTEN 完整的前列腺癌细胞不受影响，显型复制 CHD1 的遗传丢失。总体而言，本研究证明了 CHD1 染色质结构域的配体性，并表明更有效和选择性的拮抗剂可以转化为在 PTEN 缺陷型癌症中具有治疗价值的化合物。