Journal Article Review Ahead of print
PubMed: 42936580 DOI: 10.1039/d6md00337k
Recent advances in scaffold-based KRAS G12C inhibitors: SAR and biological evaluation insights.
RSC Med Chem
Authors: Tomojit Bhattacharjee, Ankush Kumar, Thakur Gurjeet Singh, Rohit Bhatia
Affiliations
- Chitkara College of Pharmacy, Chitkara University Rajpura 140401 Punjab India.
Abstract
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 IC 50 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 IC 50 = 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.
MeSH
Cells, Neoplasms, Carcinoma, Non-Small-Cell Lung, Therapeutics, Mutation, Pyrimidines