Research progress on small molecule inhibitors targeting KRAS G12C with acrylamide structure and the strategies for solving KRAS inhibitor resistance.

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.