Drug Discovery and Development, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia.
Experimental Therapeutics, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia.
Eur J Med Chem. 2021 Mar 15;214:113248. doi: 10.1016/j.ejmech.2021.113248. Epub 2021 Feb 3.
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 通过磷酸化转录因子或作为四亚基激酶模块的一部分，通过激酶模块与中介体复合物（一种高度保守的转录共激活因子）的可逆结合来调节转录。在各种类型的人类癌症中都发现了 CDK8 的失调，而 CDK8 在抑制自然杀伤细胞的抗癌反应中的作用正在被理解。目前，针对 CDK8 的癌症药物备受关注。本文详细介绍了一系列新型吡啶衍生的 CDK8 抑制剂的发现。通过药物化学优化，得到了具有口服生物利用度的强效 CDK8 抑制剂 38（AU1-100）。该化合物通过抑制细胞 CDK8 的激酶活性来抑制 MV4-11 急性髓系白血病细胞的增殖。在接受 38 治疗的小鼠中未观察到全身毒性。这些结果证明 38 作为抗癌剂进一步进行临床前研究是合理的。
