Discovery of novel CDK9 inhibitors containing 1H-pyrrolo[2,3-b]pyridine moiety for treatment of colorectal cancer.

In this work, YK-2168 was selected as the lead compound for the development of a series of highly selective CDK9 inhibitors due to its unique 1H-pyrrolo[2,3-b]pyridine scaffold, which acts as an optimal backbone for targeting the kinase hinge region. The optimized compound B3 exhibited potent inhibitory activities at both enzymatic and cellular levels with satisfactory selectivity. Mechanistic studies revealed that compound B3 induces apoptosis in the HCT116 cells by suppressing the phosphorylation of RNA polymerase II at Ser2 site, which further results in the downregulates the expression of apoptosis-related gene and protein (Mcl-1) and triggers the cleavage of caspase 3 and PARP. Pharmacokinetic studies and in vivo experiments demonstrated that intravenous injection of compound B3 could achieve prominent therapeutic efficacy with a high safety profile. In general, these findings indicate that compound B3 is a promising candidate for CRC treatment.