CDK8 regulates transcription either by phosphorylation of transcription factors or, as part of a four-subunit kinase module, through a reversible association of the kinase module with the Mediator complex, a highly conserved transcriptional coactivator. Deregulation of CDK8 has been found in various types of human cancer, while the role of CDK8 in supressing anti-cancer response of natural killer cells is being understood. Currently, CDK8-targeting cancer drugs are highly sought-after. Herein we detail the discovery of a series of novel pyridine-derived CDK8 inhibitors. Medicinal chemistry optimisation gave rise to 38 (AU1-100), a potent CDK8 inhibitor with oral bioavailability. The compound inhibited the proliferation of MV4-11 acute myeloid leukaemia cells with the kinase activity of cellular CDK8 dampened. No systemic toxicology was observed in the mice treated with 38. These results warrant further pre-clinical studies of 38 as an anti-cancer agent.

CDK8通过转录因子的磷酸化或作为四亚基激酶模块的一部分，通过激酶模块与Mediator复合物（一种高度保守的转录共激活因子）的可逆结合来调节转录。已经在各种类型的人类癌症中发现了CDK8的失调，而人们已经理解了CDK8在抑制天然杀伤细胞的抗癌反应中的作用。当前，靶向CDK8的抗癌药物非常受欢迎。本文中，我们详细介绍了一系列新型吡啶衍生的CDK8抑制剂的发现。药物化学优化产生了38（AU1-100），一种具有口服生物利用度的有效CDK8抑制剂。该化合物抑制了MV4-11急性髓性白血病细胞的增殖，同时抑制了细胞CDK8的激酶活性。在用38处理的小鼠中未观察到全身毒理学。这些结果值得对38作为抗癌药进行进一步的临床前研究。