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
  • 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. [email protected].
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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