Design, synthesis, and activity evaluation of selective CDK9 inhibitors containing indazole fragments.

Targeting the inhibition of CDK9 represents a promising therapeutic strategy for colorectal cancer. This study designed and synthesized two series (A and B) of 28 unreported compounds based on rational structural modification of the lead compound AZD5438. Among them, compound B11 exhibited comparable in vitro antiproliferative activity to AZD5438 against three colorectal cancer cell lines (HCT116, RKO, and HT-29), along with superior selectivity for CDK9 inhibition, displaying an IC50 of 7.13 nM. The selective binding mode of B11 toward CDK9 was analyzed using molecular dynamics simulations and MM/GBSA calculations. Mechanistic studies demonstrated that B11 induces apoptosis in HCT116 cells by elevating intracellular ROS levels through suppression of anti-apoptotic protein expression and activating the caspase-3 pathway. In conclusion, compound B11 may serve as a novel selective CDK9 inhibitor worthy of further development for colorectal cancer treatment.