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

Recent progress in targeting KRAS 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 inhibitor. MRTX1133 demonstrated a high-affinity interaction with GDP-loaded KRAS with K and IC values of ~0.2 pM and <2 nM, respectively, and ~700-fold selectivity for binding to KRAS as compared to KRAS. MRTX1133 also demonstrated potent inhibition of activated KRAS based on biochemical and co-crystal structural analyses. MRTX1133 inhibited ERK1/2 phosphorylation and cell viability in KRAS-mutant cell lines, with median IC values of ~5 nM, and demonstrated >1,000-fold selectivity compared to KRAS cell lines. MRTX1133 exhibited dose-dependent inhibition of KRAS-mediated signal transduction and marked tumor regression (≥30%) in a subset of KRAS-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 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 mutation-positive tumors on mutant KRAS for tumor cell growth and survival.