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Related Experiment Video

Updated: May 14, 2026

Covalent Fragment Screening Using the Quantitative Irreversible Tethering Assay
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Discovery of Structurally Distinct Covalent KRAS G12C Inhibitor Scaffolds Through Large-Scale In Silico Screening and

Glen J Weiss1,2, Joseph C Loftus3, David W Mallery1

  • 1International Genomics Consortium, Phoenix, AZ 85014, USA.

Cancers
|May 13, 2026
PubMed
Summary

Researchers identified novel covalent KRAS G12C inhibitors by screening millions of molecules. These new compounds offer distinct scaffolds to overcome resistance to current therapies, advancing targeted cancer treatment options.

Keywords:
KRAS G12CMM/GBSAcovalent inhibitorsmolecular dynamicsoncology drug discoveryresistanceswitch-II pocketvirtual screening

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Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Computational Biology

Background:

  • KRAS G12C mutations are key targets in solid tumors, especially non-small cell lung cancer.
  • Existing covalent inhibitors face resistance, necessitating novel inhibitor scaffolds.

Purpose of the Study:

  • Identify novel covalent binders for the KRAS G12C switch-II pocket.
  • Utilize large-scale in silico screening and experimental validation.

Main Methods:

  • Screened over 1.9 million small molecules using covalent docking.
  • Employed multi-stage refinement including molecular dynamics and MM/GBSA.
  • Validated candidates using cellular NanoBRET target-engagement assays.

Main Results:

  • Prioritized 50 compounds across distinct chemical scaffolds.
  • Demonstrated favorable predicted binding and stable interactions.
  • Identified novel inhibitors with sub-micromolar KRAS G12C engagement and low cytotoxicity.

Conclusions:

  • Discovered structurally distinct KRAS G12C inhibitor chemotypes.
  • These compounds serve as starting points for next-generation targeted therapies.