Identification of Novel 2‑(Azetidin-3-ylamino)-nicotinamide Derivatives as Potent KRAS::SOS1 Inhibitors

Son of Sevenless 1 (SOS1), the principal guanine nucleotide exchange factor for KRAS activation, has emerged as a promising therapeutic target for KRAS-driven cancers. Utilizing structure-based drug design, we discovered a novel class of nicotinamide derivatives incorporating strategically positioned basic groups that engage with an acidic region in the SOS1 protein. The representative compound 12f showed potent biochemical activity and 3D cellular antiproliferative activity and minimal hERG inhibition. Despite the suboptimal pharmacokinetic profile, this series represents structurally distinct SOS1 inhibitors with a new binding mode, providing valuable insights for future SOS1 inhibitor designs.