Research progress on small molecule inhibitors targeting KRAS G12C with acrylamide structure and the strategies for solving KRAS inhibitor resistance
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Updated: Jul 4, 2025
Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein
Published on: January 16, 2020
Zhiyan Jiang1, Yan Li1, Xin Zhou1
1Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China.
Abstract:
KRAS (Kirsten-RAS) is a highly mutated gene in the RAS (rat sarcoma) gene family that acts as a critical switch in intracellular signaling pathways, regulating cell proliferation, differentiation, and survival. The continuous activation of KRAS protein resulting from mutations leads to the activation of multiple downstream signaling pathways, inducing the development of malignant tumors. Despite the significant role of KRAS in tumorigenesis, targeted drugs against KRAS gene mutations have failed, and KRAS was once considered an undruggable target. The development of KRAS G12C mutant conformational modulators and the introduction of Sotorasib (R&D code: AMG510) have been a breakthrough in this field, with its remarkable clinical outcomes. Consequently, there is now a great number of KRAS G12C mutations. Patent applications for mutant GTPase KRAS G12C inhibitors, which are said to be covalently modified by cysteine codon 12, have been submitted since 2014. This review classifies KRAS G12C inhibitors based on their chemical structure and evaluates their biological properties. Additionally, it discusses the obstacles encountered in KRAS inhibitor research and the corresponding solutions.
Insights
KRAS G12C inhibitors represent a breakthrough in cancer therapy, targeting a previously undruggable mutation. This review classifies these inhibitors and discusses challenges and solutions in their development.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- KRAS mutations are prevalent in cancer, driving uncontrolled cell growth.
- KRAS was historically considered an undruggable target due to difficulties in developing effective therapies.
- The KRAS G12C mutation is a significant driver in various malignancies.
Purpose of the Study:
- To review and classify KRAS G12C inhibitors based on chemical structure.
- To evaluate the biological properties of these inhibitors.
- To discuss challenges and potential solutions in KRAS inhibitor research.
Main Methods:
- Literature review of KRAS G12C inhibitors.
- Classification of inhibitors by chemical structure.
- Evaluation of inhibitor biological properties and clinical outcomes.
Main Results:
- Development of KRAS G12C mutant conformational modulators, like Sotorasib, has shown clinical success.
- Numerous patent applications for KRAS G12C inhibitors have been filed since 2014.
- Inhibitors covalently modify cysteine codon 12 in the mutant KRAS GTPase.
Conclusions:
- KRAS G12C inhibitors offer a promising therapeutic strategy for cancers with this mutation.
- Continued research is essential to overcome obstacles in developing and optimizing KRAS inhibitors.
- Understanding inhibitor chemistry and biology is key to advancing targeted cancer therapy.
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