Insilico Medicine Shanghai Ltd, Suite 902, Tower C, Changtai Plaza, 2889 Jinke Road, Pudong New District, Shanghai 201203, China.
Insilico Medicine Hong Kong Ltd., Hong Kong Science and Technology Park, Hong Kong 999077, China.
J Med Chem. 2024 May 23;67(10):8161-8171. doi: 10.1021/acs.jmedchem.4c00248. Epub 2024 May 1.
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 , 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 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.
介导激酶 CDK8 和 CDK19 控制着对各种信号做出响应的特定基因的动态转录，并且已经被证明可以被各种实体瘤和液体瘤劫持来维持过度增殖。CDK8/19 正成为一种很有前途的抗癌治疗靶点。在这里，我们报告了化合物 的发现，这是一种新型的小分子 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 和激酶组谱中具有显著的选择性。此外，化合物 在多种临床前物种中还表现出良好的 ADME 特征，包括对 CYP1A2 的抑制作用低、清除率可接受和口服生物利用度高。在小鼠模型中的强大的体内 PD 和疗效研究进一步证明了它作为单一和联合治疗癌症的潜力。
