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

Publication Type:

Journal Article


Nat Med, Volume 28, Issue 10, p.2171-2182 (2022)


Carcinoma, Pancreatic Ductal, Cell Line, Tumor, ErbB Receptors, Humans, Mutation, Pancreatic Neoplasms, Proto-Oncogene Proteins p21(ras)


<p>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&thinsp;pM and &lt;2&thinsp;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&thinsp;nM, and demonstrated &gt;1,000-fold selectivity compared to KRAS cell lines. MRTX1133 exhibited dose-dependent inhibition of KRAS-mediated signal transduction and marked tumor regression (&ge;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.</p>