KRAS mutations are the most common mutations. Especially, the KRAS oncogene encodes a binding protein that plays a crucial role in transmitting signals from extracellular growth factors to the cell nucleus. KRAS mutations occur commonly in colorectal carcinomas. KRAS^G12C mutations are present in lung and colon adenocarcinoma as well as smaller fractions of other cancers. MRTX849 is a potent and selective inhibitor of KRAS^G12C, KRAS-dependent signal transduction and cell viability in vitro.

MRTX849 is an Orally Active and Covalent Inhibitor of KRAS G12C.

It covalently binds to KRAS^G12C at the cysteine 12 residue, locks the protein in its inactive GDP-bound conformation, inhibits KRAS-dependent signaling and elicit anti-tumor responses in tumor models. In the KRAS^G12C-mutant H358 lung and MIA PaCa-2 pancreatic cancer cell lines, MRTX849 demonstrates an upward electrophoretic mobility shift of KRAS^G12C protein band migration by immunoblot, indicative of covalent modification of KRAS^G12C. MRTX849 also inhibits KRAS-dependent signaling targets including ERK1/2 phosphorylation (Thr202/Tyr204 ERK1; pERK), S6 phosphorylation (RSK-dependent Ser235/236; pS6) and expression of the ERK-regulated DUSP6. The evaluation of pERK over a time course of 48 hours indicates maximal inhibition is at 24 hours.

MRTX849 treatment in vivo leads to dose-dependent KRAS^G12C modification, KRAS pathway inhibition, and anti-tumor efficacy. Moreover, MRTX849 demonstrates moderate plasma clearance and prolongs half-life following oral administration. MRTX849 also demonstrates marked inhibition of ERK1/2 and S6S235/36 phosphorylation after one or three daily doses at 6 or 24 hours and levels gradually recovered by 72 hours after the final dose. Furthermore, MRTX849 demonstrates broad-spectrum tumor regression in the KRAS^G12C cell line and patient-derived xenograft models.

All in all, MRTX849 provides insight into the therapeutic susceptibility of KRAS mutant cancers.