MRTX1133 is a potent and selective KRAS G12D inhibitor that targets KRAS G12D protein in both the active and inactive states. In preclinical studies, MRTX1133 exhibited a long half-life, was able to bind to KRAS G12D protein in both active and inactive states, and selectively inhibited KRAS G12D-mutated cancer cells. In G12D mutant tumor models, it showed dose-dependent selective inhibition of the KRAS pathway and tumor regression.
MRTX1133 is a potent KRASG12D inhibitor. Treatment by intraperitoneal (IP) administration is effective against tumours in xenograft mice with KRASG12D mutations. However, MRTX1133 has low oral bioavailability (only 0.5%), which may be related to gastrointestinal malabsorption. In addition, MRTX1133 has two hydrogen bond donors (HBDs): a phenolic group and a secondary amine moiety. And the secondary amine molecule is considered to be the main cause of malabsorption. Currently, an oral prodrug of MRTX1133 has been developed to effectively treat tumours in xenograft mice with the KRASG12D mutation[1].
MRTX1133 is primarily used in studies targeting advanced solid tumours with KRASG12D mutations, such as human pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC) and colorectal cancer.
MRTX1133 is a noncovalent, potent, and selective KRAS G12D inhibitor. It optimally fills the switch II pocket and extends three substituents to favorably interact with the protein, resulting in an estimated KD against KRAS G12D of 0.2 pM. MRTX1133 prevents SOS1-catalyzed nucleotide exchange and/or formation of the KRAS G12D/GTP/RAF1 complex, thereby inhibiting mutant KRAS-dependent signal transduction. This inhibitor selectively inhibits KRAS G12D mutants but not KRAS wild-type tumor cells. MRTX1133 has single-digit nanomolar activity in cellular assays and marked in vivo efficacy in tumor models harboring KRAS G12D mutations.
Dry, dark and at 0-4℃ for short term (days to weeks) or -20℃ for long term (months to years).
[1] XIANG JI*, JIASHENG LU*; Discovery of Prodrug of MRTX1133 as an Oral Therapy for Cancers with KRASG12D Mutation[J]. ACS Omega, 2023. DOI:10.1021/acsomega.3c00329.
