RO7538483

RO7538483 (also known as RG6354) is an investigational, orally bioavailable small molecule inhibitor developed by Roche that selectively targets the **active (GTP-bound) "ON" state** of the **KRAS G12C** mutant protein. KRAS is a GTPase that acts as a molecular switch in cell signaling; mutations like G12C lock the protein in a state that promotes uncontrolled cell proliferation in various cancers, including non-small cell lung cancer (NSCLC) and colorectal cancer. While first-generation KRAS G12C inhibitors bind to the inactive "OFF" state, RO7538483 is designed to inhibit the protein while it is actively signaling, potentially overcoming resistance mechanisms and providing deeper clinical responses. It is currently in Phase 1 clinical development for the treatment of advanced solid tumors harboring the KRAS G12C mutation.