Development and biological evaluation of novel SOS1 inhibitors featuring 5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one...

SOS1 plays a pivotal role in RAS activation and has emerged as a promising therapeutic target for tumors driven by KRAS mutations. In this study, we designed and synthesized a novel series of SOS1 inhibitors based on the 5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one scaffold. Biological evaluation revealed that most compounds displayed anti-proliferative activity against K562 leukemia cells. Among these, A15f and B5a emerged as the most potent compounds comparable to BI-3406. A15f and B5a exhibited inhibitory activity against KRAS-G12C/SOS1 complex formation, with IC₅₀ value of 40.28 and 11.11 nM respectively and led to a dose-dependent decrease in pERK levels. The combination therapy of KRAS G12C inhibitor and A15f shows enhanced in vitro efficacy. Molecular docking revealed that these two compounds shared a conserved binding mode with SOS1, similar to the reported inhibitors. These findings provide foundation for further development of SOS1-targeted anticancer therapeutics and offer valuable insights for structural optimization of this novel class of inhibitors.