Design and synthesis of a 1,3,6-trimethyl-1H-benzo[d]imidazole-5-sulfonamide derivative as a type I CDK8 inhibitor against colorectal cancer.

CDK8, a member of the cyclin-dependent kinase family, is essential for regulation of Wnt/β-catenin pathway-dependent transcription and transformation processes. Here, we designed and synthesized a series of new scaffolds based on structure-based drug design (SBDD). Among them, compound 67j with 1,3,6-trimethyl-1H-benzo[d]imidazole-5-sulfonamide moiety exhibits good inhibitory activity with an IC50 value of 70.5 ± 2.6 nM. It is a type I inhibitor of CDK8 and also shows excellent anti-proliferative activity against colorectal cancer cell lines. It can also reduce the volume of colorectal cancer tumors and exhibits good anti-tumor activity in vivo. Compound 67j significantly modulated the Wnt/β-catenin pathway and the expression of its target genes both in vivo and in vitro, while also suppressing TCF/LEF transcriptional activity mediated by the Wnt/β-catenin signaling pathway. It also arrests the cell cycle of HCT-116 cells at the G2/M phase and S phase and increases their reactive oxygen species levels. Additionally, compound 67j exhibited low toxicity and favorable oral bioavailability (F = 32.4 ± 1.72 %). These results provide a basis for the research on novel scaffold type I CDK8 inhibitors and contribute to the research and development of lead compounds for the treatment of colorectal cancer.