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Updated: Apr 23, 2026

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
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Evolution of structure-guided drug design strategies targeting mutations in codon 12 of KRAS

Sadaf Dorandish1, Komal Bhayekar1, Anuradha Singh2

  • 1Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University Detroit MI 48201 USA ngavande@wayne.edu +1 (313) 577 2033 +1(313) 577 1523.

RSC Medicinal Chemistry
|June 6, 2025
PubMed

Insights

KRAS G12 mutations drive many cancers. New small-molecule inhibitors directly target these KRAS mutations, transforming this once-difficult target into a promising therapeutic opportunity for cancer patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • KRAS mutations at codon 12 are frequent oncogenic drivers associated with aggressive cancers and poor outcomes.
  • KRAS has historically been challenging to target due to its strong GDP/GTP binding and lack of druggable pockets.
  • Recent advances have yielded selective small-molecule inhibitors for KRAS G12 mutations.

Purpose of the Study:

  • To review the development of KRAS-targeted inhibitors.
  • To highlight milestones and current challenges in KRAS-targeted drug discovery.
  • To discuss evolving strategies for targeting KRAS-driven cancers.

Main Methods:

  • Review of pioneering work and significant milestones in KRAS inhibitor development.
  • Focus on structure-guided drug design and covalent inhibitor identification.
  • Analysis of direct and indirect KRAS inhibitor strategies.

Main Results:

  • Development of direct small-molecule inhibitors targeting KRAS G12 mutations, including KRAS G12C.
  • Identification of inhibitors for KRAS G12C in both GDP-bound and GTP-bound states.
  • Advancements in understanding KRAS mutations and potential for gene therapy.

Conclusions:

  • KRAS is transitioning from an elusive target to a tractable therapeutic opportunity.
  • Targeted KRAS inhibition offers new hope for patients with KRAS-driven cancers.
  • Continued research in inhibitor design and structure-based approaches is crucial.

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