Discovery of the Novel 1 H-Pyrrolo[2,3- b]pyridine Derivative as a Potent Type II CDK8 Inhibitor against Colorectal Cancer

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 22, (3-(3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)propenamide), was discovered as a potent type II CDK8 Inhibitor, which exhibited potent kinase activity with an IC₅₀ 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 (F = 39.8%). These results could provide the reference for design of new type II CDK8 inhibitors against colorectal Cancer.