Anti-tumor efficacy of a potent and selective non-covalent KRASG12D 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 similar to 0.2 pM and <2 nM, respectively, and similar to 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 similar to 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 PI3K alpha, 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.

Automated summary

This study evaluated the mechanism and anti-tumor efficacy of MRTX1133, a non-covalent KRAS(G12D) inhibitor. Results showed that MRTX1133 had a high-affinity interaction with KRAS(G12D) and inhibited its activation, leading to tumor regression. Co-targeting additional pathways enhanced the anti-tumor activity.