Related Experiment Video

Updated: Sep 14, 2025

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

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A neomorphic protein interface catalyzes covalent inhibition of RASG12D aspartic acid in tumors

Caroline Weller1, G Leslie Burnett1, Lingyan Jiang1

  • 1Revolution Medicines, Inc., Redwood City, CA, USA.

Science (New York, N.Y.)
|July 24, 2025
PubMed

Insights

Researchers developed novel covalent inhibitors targeting KRASG12D cancer by creating a unique protein interaction. This approach enables potent drug delivery, showing promise in preclinical cancer models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Mutant RAS proteins, particularly KRASG12D, are key drivers in numerous human cancers.
  • Targeting KRASG12D with covalent inhibitors is challenging due to low reactivity and high abundance of similar molecules in the body.

Purpose of the Study:

  • To overcome the challenges in covalently targeting KRASG12D.
  • To develop novel inhibitors with enhanced selectivity and efficacy against KRASG12D-driven cancers.

Main Methods:

  • Developed compounds that bind to cyclophilin A (CYPA).
  • Engineered a novel protein-protein interface between CYPA and active RAS.
  • Utilized this interface to enhance the reaction rate of covalent inhibitors with low intrinsic reactivity.

Main Results:

  • Achieved selective, enzyme-like rate enhancement for covalent modification of RASG12D.
  • Developed orally bioavailable compounds demonstrating significant antitumor activity in preclinical models.
  • Identified zoldonrasib (RMC-9805) as a promising investigational agent currently in clinical trials.

Conclusions:

  • The CYPA-RAS binding strategy effectively overcomes limitations in targeting KRASG12D.
  • This approach yields potent and selective covalent inhibitors for KRASG12D-driven cancers.
  • The findings support the clinical development of novel therapeutics for challenging cancer mutations.

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