Novel potent SOS1 inhibitors containing a tricyclic quinazoline scaffold: a joint view of experiments and simulations

Small molecules that possess the ability to regulate the interactions between Son of Sevenless 1 (SOS1) and Kristen rat sarcoma (KRAS) offer immense potential in the realm of cancer therapy. In this study, we present a novel series of SOS1 inhibitors featuring a tricyclic quinazoline scaffold. Notably, we have identified compound 8d, which demonstrates the highest potency with an IC₅₀ value of 5.1 nM for disrupting the KRAS:SOS1 interaction. Compound 8d exhibits a promising pharmacokinetic profile and achieves a remarkable 70.5% inhibition of tumor growth in pancreas tumor xenograft models. Furthermore, molecular dynamic simulations have unveiled that the tricyclic quinazoline derivatives exhibit extensive interaction with Tyr884, a crucial residue for the recognition between SOS1 and KRAS. Our findings provide fresh insights into the design of future SOS1 inhibitors, paving the way for innovative therapeutic strategies.