The mediator kinases CDK8 and CDK19 control the dynamic transcription of selected genes in response to various signals and have been shown to be hijacked to sustain hyperproliferation by various solid and liquid tumors. CDK8/19 is emerging as a promising anticancer therapeutic target. Here, we report the discovery of compound 12, a novel small molecule CDK8/19 inhibitor. This molecule demonstrated not only decent enzymatic and cellular activities but also remarkable selectivity in CDK and kinome panels. Besides, compound 12 also displayed favorable ADME profiles including low CYP1A2 inhibition, acceptable clearance, and high oral bioavailability in multiple preclinical species. Robust in vivo PD and efficacy studies in mice models further demonstrated its potential use as mono- and combination therapy for the treatment of cancers.

中文翻译：

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发现一种新型有效的细胞周期蛋白依赖性激酶 8/19 (CDK8/19) 抑制剂用于治疗癌症

介质激酶 CDK8 和 CDK19 响应各种信号控制选定基因的动态转录，并已被证明被各种实体和液体肿瘤劫持以维持过度增殖。 CDK8/19 正在成为一个有前景的抗癌治疗靶点。在这里，我们报告了化合物12的发现，这是一种新型小分子 CDK8/19 抑制剂。该分子不仅表现出良好的酶和细胞活性，而且在 CDK 和激酶组组中具有显着的选择性。此外，化合物12还表现出良好的 ADME 特性，包括低 CYP1A2 抑制、可接受的清除率以及在多个临床前物种中的高口服生物利用度。小鼠模型中稳健的体内 PD 和疗效研究进一步证明了其作为治疗癌症的单一疗法和联合疗法的潜在用途。