MRTX1133 — Investigational Agent
KRAS Inhibitor · Phase 1/2 · Mirati Therapeutics / Bristol Myers Squibb (BMS)
Mechanism of Action
Highly selective, non-covalent small molecule inhibitor of KRAS G12D. Binds the switch-II pocket of KRAS G12D via hydrogen bonding with the mutant aspartate-12 residue, locking KRAS in an inactive conformation and blocking downstream RAS-MAPK and PI3K-AKT signaling. Unlike G12C inhibitors (sotorasib, adagrasib) which form an irreversible covalent bond with a cysteine, MRTX1133 uses a reversible non-covalent mechanism targeting aspartate. It is isoform-specific and does NOT inhibit KRAS G12C, KRAS G13D, NRAS, HRAS, or wild-type KRAS.
Investigational Indications
- KRAS G12D-mutant pancreatic ductal adenocarcinoma (PDAC)
- KRAS G12D-mutant non-small cell lung cancer (NSCLC)
- KRAS G12D-mutant colorectal cancer (CRC)
- Other KRAS G12D-mutant solid tumors