SHY-867

SHY-867 is a novel small-molecule inhibitor designed to target the Ras superfamily of small GTPases, including K-Ras, RAB5A, and RAB35. Developed by Shionogi, the compound distinguishes itself from earlier Ras inhibitors by binding non-covalently to the GTP-binding pocket (orthosteric site) rather than the switch II pocket or specific mutant residues. By competing directly with GTP, SHY-867 acts as a pan-Ras inhibitor, demonstrating the ability to suppress downstream signaling and cellular proliferation in both wild-type and mutant K-Ras-expressing human cancers, such as pancreatic and non-small cell lung cancer (NSCLC). This approach addresses the historical challenge of the high binding affinity of Ras for GTP, which previously led to the protein being labeled as "undruggable."