Related Experiment Video

Updated: Jul 20, 2025

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

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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Simultaneous Covalent Modification of K-Ras(G12D) and K-Ras(G12C) with Tunable Oxirane Electrophiles

Zhongtang Yu1,2,3, Xiaoqiang He1,2,3, Ruiliu Wang1,2,3

  • 1International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development (MOE), Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.

Journal of the American Chemical Society
|August 3, 2023
PubMed

Insights

Researchers developed the first targeted covalent inhibitors (TCIs) for K-Ras(G12D) and K-Ras(G12C) cancer mutations. This breakthrough enables new dual covalent inhibitor development for difficult-to-treat cancers.

Area of Science:

  • Medicinal Chemistry
  • Oncology
  • Molecular Biology

Background:

  • Targeted covalent inhibitors (TCIs) offer advantages over noncovalent inhibitors in cancer therapy.
  • K-Ras mutations are key targets in various cancers, with K-Ras(G12D) accounting for a significant portion.
  • Existing covalent inhibitors do not target the K-Ras(G12D) mutation due to the residue's low nucleophilicity.

Purpose of the Study:

  • To develop the first compound capable of covalently inhibiting both K-Ras(G12D) and K-Ras(G12C) mutants.
  • To address the unmet need for covalent inhibitors targeting the K-Ras(G12D) mutation.

Main Methods:

  • Development of a novel covalent inhibitor.
  • Proteome profiling to assess compound conjugation and target engagement.
  • In situ functional modulation studies.

Main Results:

  • The novel compound successfully engages and covalently binds to both K-Ras(G12D) and K-Ras(G12C) mutants.
  • Proteome profiling confirmed effective conjugation with the target G12C and G12D residues.
  • The compound modulates protein functions in situ.

Conclusions:

  • This study presents the first dual covalent inhibitor for K-Ras(G12D) and K-Ras(G12C).
  • The findings provide a novel strategy for developing targeted covalent inhibitors against challenging K-Ras mutations.
  • This opens new therapeutic avenues for cancers driven by these specific K-Ras mutations.

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