School of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, P. R. China.
J Med Chem. 2022 Sep 22;65(18):12095-12123. doi: 10.1021/acs.jmedchem.2c00820. Epub 2022 Sep 6.
Few targeted drugs were approved for treatment of colorectal cancer (CRC). Cyclin-dependent kinase 8 played a vital role in regulating transcription and was a key colorectal oncogene associated to colorectal cancer. Here, through de novo drug design and in depth structure-activity relationship analysis, title compound , (3-(3-(1-pyrrolo[2,3-]pyridin-5-yl)phenyl)--(4-methyl-3-(trifluoromethyl)phenyl)propenamide), was discovered as a potent type II CDK8 inhibitor, which exhibited potent kinase activity with an IC value of 48.6 nM and could significantly inhibit tumor growth in xenografts of CRC in vivo. Further mechanism studies indicated that it could target CDK8 to indirectly inhibit β-catenin activity, which caused downregulation of the WNT/β-catenin signal and inducing cell cycle arrest in G2/M and S phases. More importantly, the title compound exhibited low toxicity with good bioavailability ( = 39.8%). These results could provide the reference for design of new type II CDK8 inhibitors against colorectal cancer.
目前仅有少数几种靶向药物被批准用于治疗结直肠癌（CRC）。细胞周期蛋白依赖性激酶 8 在转录调控中发挥着重要作用，是一种关键的结直肠致癌基因，与结直肠癌有关。在这里，通过从头药物设计和深入的结构-活性关系分析，发现标题化合物（3-（3-（1-吡咯并[2,3-]吡啶-5-基）苯基）-（4-甲基-3-（三氟甲基）苯基）丙烯酰胺）是一种有效的 II 型 CDK8 抑制剂，对激酶具有很强的抑制活性，IC 值为 48.6 nM，能够显著抑制 CRC 异种移植瘤在体内的生长。进一步的机制研究表明，它可以靶向 CDK8 来间接抑制β-catenin 的活性，从而导致 WNT/β-catenin 信号下调，并诱导细胞周期停滞在 G2/M 和 S 期。更重要的是，标题化合物表现出低毒性和良好的生物利用度（=39.8%）。这些结果可为设计新型 II 型 CDK8 抑制剂治疗结直肠癌提供参考。
