Discovery, Optimization, and Evaluation of Potent and Selective PDGFRβ Inhibitors for the Treatment of Hepatocellular Carcinoma

Platelet-derived growth factor receptors (PDGFRs), recognized as key oncogenic drivers in hepatocellular carcinoma (HCC), play crucial roles in regulating cancer cell proliferation, differentiation and migration. Although PDGFRβ is implicated in HCC progression, highly selective PDGFRβ inhibitors are still scarce. Herein, we report the discovery of novel and selective PDGFRβ inhibitors A42, A43, A45, and A46 through structure-based optimization. Among these, A45 showed the highest selectivity, with a selectivity factor of 20.7. Based on cellular antiproliferative activity and cytotoxicity profiles, the moderately selective compound A42 was selected for further investigation. A42 significantly inhibited the proliferation, colony formation and migration of HCC cells and induced substantial apoptosis. Furthermore, A42 demonstrated a favorable safety profile and promising pharmacokinetic properties with an oral bioavailability of 43.47% and significantly inhibited tumor growth in the Huh-7 xenograft tumor model. Collectively, these results suggest that A42 may serve as a promising therapeutic candidate for HCC treatment.