MRTX849 | Covalent KRAS^G12C Inhibitor

MRTX849 (2326521-71-3) is a potent (IC₅₀’s = 14 nM NCI-H358; 5 nM MIA PaCa-2) and selective (over 463 proteins @ 1 µM) covalent KRAS^G12C inhibitor.¹ It showed pronounced tumor regression in 17 of 26 KRAS^G12C-positive cell lines and xenograft models from multiple tumor types.² MTRTX849 reversed the immunosuppressive tumor environment in a genetically modified mouse model and sensitized tumors to checkpoint inhibitor therapy in a genetically modified mouse KRAS^G12C lung adenocarcinoma model.³ It reversed ABCB1-mediated multidrug resistance in vitro and in vivo ^via attenuation of ABCB1 efflux in drug-resistant cancer cells.⁴

References/Citations:

1. Fell et al. (2020), Identification of the Clinical Development Candidate MRTX849, a Covalent KRAS^G12C Inhibitor for the Treatment of Cancer; J. Med. Chem. 63 6679
2. Hallin et al. (2020); The KRAS^G12C Inhibitor, MRTX849, Provides Insight Toward Therapeutic Susceptibility of KRAS Mutant Cancers in Mouse Models and Patients, Cancer Discov., 10 54
3. Briere et al. (2021); The KRAS^G12C Inhibitor MRTX849 Reconditions the Tumor Immune Microenvironment and Sensitizes Tumors to Checkpoint Inhibitor Therapy, Mol. Cancer Ther., 20 975
4. Zhang et al. (2022); Adagrasib, a KRAS G12C inhibitor, reverses the multidrug resistance mediated by ABCB1 in vitro and in vivo, Cell Commun. Signal., 20 142