Recent advance of KRAS-G12C inhibitors for cancer therapy

Abstract

The RAS gene family encodes key oncoproteins that play a central role in cellular signal transduction and tumorigenesis. KRAS exhibits the highest mutation frequency in human cancers, accounting for approximately 80 % of RAS-driven malignancies, with the glycine-to-cysteine substitution at codon 12 (G12C) being one of the most prevalent oncogenic variants. RAS proteins regulate downstream signaling pathways by modulating transcription and translation processes, while at the cellular level, they promote malignant phenotypes such as uncontrolled proliferation and metastasis, making them critical therapeutic targets. In 2021, the FDA approved AMG510 (Sotorasib), the first covalent inhibitor targeting the KRAS-G12C mutation. Nevertheless, emerging resistance mechanisms necessitate continuous medicinal chemistry innovations. Currently, many highly KRAS-G12C inhibitors have been approved or are undergoing various clinical stages. This review provides an overview of contemporary medicinal chemistry approaches in KRAS-G12C inhibitor development. The collective insights from this analysis, combined with existing literature, provide valuable frameworks for designing novel KRAS-G12C targeted therapeutics.

Keywords: Cancer therapy; Drug resistance; KRAS-G12C; Targeted therapy.