For decades, KRAS was considered undruggable — a death sentence for patients whose tumors carried mutations in this master oncogene, which drives roughly a quarter of all human cancers. The emergence of molecular glue strategies now represents one of the most structurally creative shifts in oncology pharmacology, potentially rewriting treatment prospects for lung, pancreatic, and colorectal cancers where standard therapies routinely fail.
This review in Acta Pharmacologica Sinica traces the conceptual and chemical evolution of KRAS-targeting molecular glues — small molecules that work not by blocking an active site but by artificially stabilizing protein–protein interactions or forcing aberrant ones. Early compounds in this class were allele-selective, designed specifically for the G12C mutation that creates a reactive cysteine pocket; sotorasib and adagrasib exemplify this first generation. The field has since advanced toward compounds capable of engaging multiple RAS family members simultaneously — so-called Pan-RAS glues — and toward modulators that rewire entire signaling complexes by altering how KRAS interacts with effector proteins like SOS1 and RAF. These newer agents exploit cryptic binding surfaces and induced-fit pockets invisible to classical drug design.
The significance here extends well beyond mechanistic novelty. The G12C-selective inhibitors, while clinically approved, cover only roughly 13% of KRAS-mutant lung adenocarcinomas and a far smaller fraction in pancreatic cancer, where G12D and G12V dominate. Pan-RAS approaches could theoretically address this unmet majority. That said, this review synthesizes preclinical and early-stage findings; the clinical durability of pan-RAS glues remains untested at scale, resistance mechanisms are already emerging against first-generation compounds, and the selectivity challenge — avoiding disruption of wild-type RAS signaling essential for normal cell function — is formidable. Still, as a conceptual roadmap, this work is genuinely paradigm-relevant for medicinal chemists and oncologists tracking the next frontier in RAS biology.