Related Experiment Video

Updated: Oct 10, 2025

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
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Identification of MRTX1133, a Noncovalent, Potent, and Selective KRASG12D Inhibitor

Xiaolun Wang1, Shelley Allen2, James F Blake2

  • 1Mirati Therapeutics, San Diego, California 92121, United States.

Journal of Medicinal Chemistry
|December 10, 2021
PubMed

Insights

Researchers discovered MRTX1133, the first noncovalent inhibitor targeting the KRASG12D mutation. This potent and selective drug shows efficacy in preclinical models, offering a new therapeutic avenue for KRASG12D-driven cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • KRASG12D is a prevalent oncogenic mutation driving solid tumor growth.
  • Targeting KRASG12D is challenging due to the need for high-affinity, non-covalent inhibitors.
  • Existing therapies often target other KRAS mutations like KRASG12C.

Purpose of the Study:

  • To discover and characterize the first non-covalent inhibitor of KRASG12D.
  • To develop a potent and selective therapeutic agent against KRASG12D mutations.
  • To evaluate the efficacy of the novel inhibitor in a relevant preclinical model.

Main Methods:

  • Structure-based drug design and activity improvement.
  • Biochemical and cellular assays for inhibitor characterization.
  • In vivo efficacy studies in KRASG12D mutant xenograft models.

Main Results:

  • Discovery of MRTX1133, a novel non-covalent KRASG12D inhibitor.
  • MRTX1133 demonstrates high potency and selectivity for KRASG12D.
  • Significant tumor growth inhibition observed in a KRASG12D xenograft mouse model.

Conclusions:

  • MRTX1133 represents a first-in-class non-covalent inhibitor for KRASG12D.
  • This discovery provides a promising new therapeutic strategy for KRASG12D-driven cancers.
  • Further development of MRTX1133 warrants investigation for clinical application.

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