Center of Drug Screening and Evaluation, Wannan Medical College, Wuhu, Anhui 241000, PR China.
Center of Drug Screening and Evaluation, Wannan Medical College, Wuhu, Anhui 241000, PR China; School of Pharmacy, Wannan Medical College, Wuhu, Anhui 241000, PR China.
Bioorg Med Chem Lett. 2019 Feb 15;29(4):549-555. doi: 10.1016/j.bmcl.2018.12.065. Epub 2019 Jan 2.
With the aim of discovering novel cyclin-dependent kinase 8 (CDK8) inhibitors, a combined similarity search and molecular docking approach was employed, which led to 32 hits. Biological tests led to the discovery of several novel submicromolar inhibitors. In particular, compound C768-0769 (ZC0201) showed good CDK8 inhibitory activity, and compound ZC0201 effectively suppressed HCT-116 colorectal cancer cell proliferation by inducing G1/S transition arrest. Furthermore, modulation of phosphorylated signal transducer and activator of transcription 1 (Ser 727) (STAT1), a pharmacodynamic biomarker of CDK8 activity, demonstrated that ZC0201 may cause G1/S transition arrest through CDK8 activity inhibition. Due to its good cellular activity, ZC0201 may be an ideal lead compound for further modification as a potential cancer therapeutic agent.
为了发现新型细胞周期蛋白依赖性激酶 8（CDK8）抑制剂，采用了组合相似度搜索和分子对接方法，得到了 32 个先导化合物。生物学测试发现了几种新型亚毫摩尔抑制剂。特别是化合物 C768-0769（ZC0201）表现出良好的 CDK8 抑制活性，并且通过诱导 G1/S 期转变阻滞，化合物 ZC0201 有效地抑制了结肠直肠癌细胞系 HCT-116 的增殖。此外，磷酸化信号转导和转录激活因子 1（Ser727）（STAT1）的调制，CDK8 活性的药效生物标志物，表明 ZC0201 可能通过 CDK8 活性抑制引起 G1/S 期转变阻滞。由于其良好的细胞活性，ZC0201 可能是进一步修饰的理想先导化合物，作为一种有潜力的癌症治疗剂。
