2. Academic Validation
  3. Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor

Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor

  • Nat Med. 2022 Oct;28(10):2171-2182. doi: 10.1038/s41591-022-02007-7.
Jill Hallin 1,  Vickie Bowcut 1,  Andrew Calinisan 1,  David M Briere 1,  Lauren Hargis 1,  Lars D Engstrom 1,  Jade Laguer 1,  James Medwid 1,  Darin Vanderpool 1,  Ella Lifset 1,  David Trinh 1,  Natalie Hoffman 1,  Xiaolun Wang 1,  J David Lawson 1,  Robin J Gunn 1,  Christopher R Smith 1,  Nicole C Thomas 1,  Matthew Martinson 2,  Alex Bergstrom 2,  Francis Sullivan 2,  Karyn Bouhana 2,  Shannon Winski 2,  Leo He 3,  Julio Fernandez-Banet 3,  Adam Pavlicek 3,  Jacob R Haling 1,  Lisa Rahbaek 1,  Matthew A Marx 1,  Peter Olson 1,  James G Christensen 4
Affiliations

Affiliations

  • 1 Mirati Therapeutics, Inc., San Diego, CA, USA.
  • 2 Array BioPharma, Inc. (acquired by Pfizer), Boulder, CO, USA.
  • 3 Monoceros Biosystems, LLC, San Diego, CA, USA.
  • 4 Mirati Therapeutics, Inc., San Diego, CA, USA. christensenj@mirati.com.
PMID: 36216931 DOI: 10.1038/s41591-022-02007-7
Abstract

Recent progress in targeting KRASG12C 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 KRASG12D inhibitor. MRTX1133 demonstrated a high-affinity interaction with GDP-loaded KRASG12D with KD and IC50 values of ~0.2 pM and <2 nM, respectively, and ~700-fold selectivity for binding to KRASG12D as compared to KRASWT. MRTX1133 also demonstrated potent inhibition of activated KRASG12D based on biochemical and co-crystal structural analyses. MRTX1133 inhibited ERK1/2 phosphorylation and cell viability in KRASG12D-mutant cell lines, with median IC50 values of ~5 nM, and demonstrated >1,000-fold selectivity compared to KRASWT cell lines. MRTX1133 exhibited dose-dependent inhibition of KRAS-mediated signal transduction and marked tumor regression (≥30%) in a subset of KRASG12D-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 KRASG12D 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 KRASG12D mutation-positive tumors on mutant KRAS for tumor cell growth and survival.

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