A Comprehensive Review of Allosteric KRAS-G12C Inhibitors: Structure, Mechanism of Action, Challenges, and Therapeutic Development Perspectives
| Author | Amirhossien Alamdarifar | en |
| Author | Solmaz Kia | en |
| Orcid | Amirhossien Alamdarifar [0009-0004-0458-5242] | en |
| Orcid | Solmaz Kia [0000-0002-2685-4202] | en |
| Issued Date | 2026-04-30 | en |
| Abstract | Context: KRAS-G12C has emerged as a clinically tractable oncogenic RAS mutation, establishing a new paradigm for allele-specific precision oncology. Covalent allosteric inhibitors, including sotorasib and adagrasib, have demonstrated meaningful clinical activity, particularly in advanced non-small cell lung cancer. However, intrinsic and acquired resistance limit their therapeutic efficacy. This review classifies key KRAS-G12C inhibitors according to their chemical scaffolds and binding modes, examines molecular and clinical mechanisms of resistance, and discusses emerging therapeutic strategies and future directions. Evidence Acquisition: Searches were conducted in Google Scholar and the National Center for Biotechnology Information, including PubMed where applicable. Reference lists of relevant articles were also screened to identify additional publications. Results: Current covalent KRAS-G12C inhibitors bind to the inducible switch II pocket and irreversibly stabilize the inactive guanosine diphosphate (GDP)-bound conformation, thereby suppressing downstream signaling. Resistance involves heterogeneous mechanisms, including secondary KRAS alterations, activation of bypass receptor tyrosine kinase pathways, reactivation of RAS–ERK and phosphatidylinositol 3-kinase (PI3K)–AKT signaling, and adaptive remodeling of the tumor microenvironment. Emerging approaches include next-generation covalent and noncovalent KRAS-G12C inhibitors, pan-KRAS and pan-RAS strategies, and inhibitors of Son of Sevenless homolog 1 (SOS1) and Src homology 2 domain-containing phosphatase 2 (SHP2). Rational combination regimens aim to improve therapeutic responses by simultaneously targeting upstream, downstream, and parallel survival pathways. Conclusions: KRAS-G12C inhibition represents a major advance in precision oncology, although resistance remains a central challenge. Further progress will depend on integrating improved inhibitor design with a deeper understanding of resistance biology and rational combination strategies to enhance the depth and durability of clinical responses. | en |
| DOI | https://doi.org/10.5812/gct-172151 | en |
| URI | https://brieflands.com/journals/gct/articles/172151 | en |
| Keyword | KRAS-G12C | en |
| Keyword | Allosteric Inhibitor | en |
| Keyword | Covalent Inhibitor | en |
| Keyword | Noncovalent Inhibitor | en |
| Keyword | Switch II Pocket | en |
| Keyword | Resistance | en |
| Keyword | Combination Therapy | en |
| Keyword | Pan-KRAS | en |
| Publisher | Brieflands | en |
| Title | A Comprehensive Review of Allosteric KRAS-G12C Inhibitors: Structure, Mechanism of Action, Challenges, and Therapeutic Development Perspectives | en |
| Type | Review Article | en |
Files
Original bundle
1 - 1 of 1
Loading...
- Name:
- gct-13-2-172151-publish-pdf.pdf
- Size:
- 382.07 KB
- Format:
- Adobe Portable Document Format
- Description:
- Article/s PDF