Structure-Based Design of Allosteric Inhibitors Targeting Mutant KRAS in Pancreatic Cancer
DOI:
https://doi.org/10.5281/zenodo.22638226Keywords:
KRAS, allosteric inhibitor, pancreatic cancer, structure-based drug design, switch II pockeAbstract
Background: Mutant KRAS drives over 90% of pancreatic ductal adenocarcinomas and was long considered undruggable because
of its picomolar GTP affinity and featureless surface. Objective: This review synthesises structure-based design strategies that
produced allosteric KRAS inhibitors and evaluates their relevance to pancreatic cancer. Methods: We conducted a narrative
review of published structure-based drug design, X-ray crystallography, and allosteric inhibitor development studies targeting
mutant KRAS, identified via PubMed, Google Scholar, Crossref, and bioRxiv. Findings: Discovery of a cryptic switch II pocket
enabled covalent G12C inhibitors sotorasib and adagrasib, validated crystallographically and in clinical trials including pancreatic
cohorts. Analogous switch II/switch I-adjacent pockets yielded the noncovalent G12D inhibitor MRTX1133 and related
salt-bridge-forming compounds, addressing the mutation most common in pancreatic cancer. Acquired resistance mutations and
adaptive feedback limit durability. Conclusions: Structure-guided targeting of allosteric pockets has transformed KRAS from
undruggable to clinically tractable, with G12D-selective and pan-KRAS agents now advancing specifically for pancreatic cancer.
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