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Targeting oncogenic KRasG13C with nucleotide-based covalent inhibitors.

Lisa Goebel1, Tonia Kirschner1, Sandra Koska1

  • 1Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany.

Elife
|March 27, 2023
PubMed
Summary

Researchers designed novel covalent inhibitors targeting KRasG13C, a key cancer-driving mutation. These inhibitors block oncogenic signaling, offering a new therapeutic strategy for KRasG13C-driven cancers.

Keywords:
E. coliG13CRasbiochemistrycancerchemical biologycovalent inhibitorsnucleotide analogues

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Area of Science:

  • Oncology
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • Ras proteins, including KRas, are frequently mutated in human cancers, driving tumor growth.
  • The KRasG13C mutation is a significant oncogenic driver that has historically been challenging to target therapeutically.

Purpose of the Study:

  • To design, synthesize, and evaluate novel nucleotide-based covalent inhibitors specifically for KRasG13C.
  • To investigate the molecular properties and anti-cancer potential of these inhibitors.

Main Methods:

  • Structure-based drug design and chemical synthesis of covalent inhibitors.
  • Biochemical assays, kinetic studies, and mass spectrometry to assess inhibitor properties.
  • X-ray crystallography to determine the binding mode of inhibitors with KRasG13C.
  • Cellular assays to evaluate the impact on oncogenic signaling.

Main Results:

  • Successful design and synthesis of nucleotide-based covalent inhibitors for KRasG13C.
  • Demonstration of promising molecular properties and covalent modification of KRasG13C.
  • X-ray structures reveal the first covalent complexes of KRasG13C with GDP analogs.
  • Inhibitors prevent SOS-catalyzed nucleotide exchange and block oncogenic signaling in cells.

Conclusions:

  • Nucleotide-based covalent inhibitors represent a promising therapeutic strategy for KRasG13C-driven cancers.
  • Covalent modification of KRasG13C effectively inhibits its oncogenic function.
  • This work provides a foundation for developing new targeted cancer therapies.