Discovery and Optimization of Indole-Based CDK9 Inhibitors for Hepatocellular Carcinoma

Abstract

CDK9 has emerged as a promising therapeutic target for anticancer drug development. Although multiple CDK9 inhibitors have entered clinical evaluation, differentiated scaffolds with convincing activity and tolerability in solid tumors remain limited. In this study, we identified a series of indole-based CDK9 inhibitors through virtual screening and structure-based drug design, and systematically evaluated their therapeutic potential in hepatocellular carcinoma (HCC). Among these compounds, W24 exhibited potent CDK9 inhibitory activity (IC50 = 0.9 nM) and a preliminary kinase selectivity profile. W24 effectively induced HCC cell death in vitro, which was accompanied by DNA damage and downregulation of the anti-apoptotic protein Mcl-1. Furthermore, W24 significantly suppressed tumor growth in HepG2 and Huh-7 xenograft models with an acceptable safety profile under the tested dosing regimen. Collectively, these findings highlight W24 as a promising lead compound and provide valuable insights for the development of next-generation CDK9 inhibitors for the treatment of hepatocellular carcinoma.