Anti-tumor efficacy of a potent and selective non-covalent KRAS^G12D inhibitor.

Recent progress in targeting KRAS^G12C has provided both insight and inspiration for targeting alternative KRAS mutants. In this study, we evaluated the mechanism of action and anti-tumor efficacy of MRTX1133, a potent, selective and non-covalent KRAS^G12D inhibitor. MRTX1133 demonstrated a high-affinity interaction with GDP-loaded KRAS^G12D with K_D and IC₅₀ values of ~0.2 pM and <2 nM, respectively, and ~700-fold selectivity for binding to KRAS^G12D as compared to KRAS^WT. MRTX1133 also demonstrated potent inhibition of activated KRAS^G12D based on biochemical and co-crystal structural analyses. MRTX1133 inhibited ERK1/2 phosphorylation and cell viability in KRAS^G12D-mutant cell lines, with median IC₅₀ values of ~5 nM, and demonstrated >1,000-fold selectivity compared to KRAS^WT cell lines. MRTX1133 exhibited dose-dependent inhibition of KRAS-mediated signal transduction and marked tumor regression (≥30%) in a subset of KRAS^G12D-mutant cell-line-derived and patient-derived xenograft models, including eight of 11 (73%) pancreatic ductal adenocarcinoma (PDAC) models. Pharmacological and CRISPR-based screens demonstrated that co-targeting KRAS^G12D with putative feedback or bypass pathways, including EGFR or PI3Kα, led to enhanced anti-tumor activity. Together, these data indicate the feasibility of selectively targeting KRAS mutants with non-covalent, high-affinity small molecules and illustrate the therapeutic susceptibility and broad dependence of KRAS^G12D mutation-positive tumors on mutant KRAS for tumor cell growth and survival.