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Recent advances in the development of inhibitors targeting KRAS-G12C and its related pathways

Dongqiang Zhao1, Yu Liu1, Fengchao Yi1

  • 1China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin, 300457, China.

European Journal of Medicinal Chemistry
|August 5, 2023
PubMed

Insights

KRAS mutations drive cancer, but resistance to single KRAS-G12C inhibitors like AMG510 is increasing. New therapies targeting KRAS pathways and combination treatments are crucial for overcoming drug resistance and improving cancer treatment outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • RAS genes (KRAS, HRAS, NRAS) are implicated in human tumors, with KRAS mutations found in approximately 80% of cancers.
  • KRAS regulates gene transcription, translation, cell proliferation, and migration, making it a critical factor in cancer development.
  • The KRAS-G12C mutation is a significant driver in various cancers.

Purpose of the Study:

  • To review the mechanism of action for KRAS-G12C inhibitors.
  • To explore structure-activity relationships and optimization of novel KRAS inhibitors.
  • To discuss combination therapies for overcoming drug resistance.

Main Methods:

  • Review of existing literature on KRAS inhibitors and their mechanisms.
  • Analysis of structure-activity relationships (SAR) for KRAS-G12C inhibitors.
  • Examination of preclinical and clinical data on targeted therapies and combination strategies.

Main Results:

  • AMG510, a KRAS-G12C inhibitor, demonstrated efficacy but faces challenges due to increasing drug resistance.
  • Development of novel inhibitors targeting upstream and downstream pathways of KRAS is ongoing.
  • Combination therapies show promise in enhancing anti-tumor effects and overcoming resistance.

Conclusions:

  • Targeting the KRAS-G12C mutation is a validated therapeutic strategy, but resistance necessitates further research.
  • Optimizing inhibitor design and exploring combination therapies are essential for improving patient outcomes in KRAS-mutated cancers.
  • Continued investigation into KRAS pathway modulation offers significant potential for next-generation cancer treatments.

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