Recent advances in scaffold-based KRAS^G12C inhibitors: SAR and biological evaluation insights

Over the past decade, targeting Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations has shifted from being considered an undruggable target to becoming a realistic therapeutic strategy with the development of KRAS^G12C inhibitors. This mutation replaces glycine with cysteine at codon 12, thereby reducing the GTPase activity by keeping the protein in its active GTP-bound state. This process activates downstream RAF-MEK-ERK and PI3K-AKT signalling pathways and plays a crucial role in driving various cellular processes such as uncontrolled cell proliferation and survival in cancers, including non-small cell lung cancer (NSCLC), colorectal cancer, and pancreatic cancer. In the present review, various KRAS^G12C inhibitors reported in the last five years are compiled according to their structural class, including quinazolines, pyrimidines, pyrido-pyrimidinones, and pyrrole-pyrimidines, along with PROTAC-based degraders. Among these, compound 12 exhibited strong antiproliferative activity against the KRAS^G12C-mutant H358 cell line with an IC₅₀ value of 7.6 nM. The presence of a 2-fluorophenyl moiety made compound 12 the most active compound. Compound 18 was also identified as a highly effective PROTAC degrader with IC₅₀ = 0.045 μM (45 nM) in MIA PaCa-2 cells. Structure-activity relationship (SAR) analysis demonstrated that electrophilic warheads (acrylamide moieties) together with rigid heterocyclic scaffolds play a key role in enhancing potency and selectivity. Additionally, docking studies, biological evaluations, and in vivo findings are discussed to provide a clearer picture of the therapeutic potential of various KRAS^G12C inhibitors. Overall, the present review highlights the recent progress in the development of KRAS^G12C inhibitors for the treatment of cancer.