{"entity":{"id":"paper-ostrem-kras-g12c-nature-2013","kind":"paper","name":"Ostrem and Shokat: the hidden pocket that made KRAS G12C druggable","aka":[],"tldr":"Using disulfide-tethering screens, Shokat's laboratory found small molecules that bind covalently to the mutant cysteine of KRAS G12C in a previously unknown pocket beneath switch II, locking the oncoprotein in its inactive GDP-bound state.","summary":"KRAS had been considered undruggable for three decades because it binds GTP with picomolar affinity and has no obvious deep pocket. Ostrem and colleagues exploited the cysteine introduced by the G12C mutation, present in about 13% of lung adenocarcinomas, screening a library of cysteine-reactive fragments by tethering.\n\nCrystal structures revealed that the hits bound in a cryptic pocket (switch-II pocket, S-IIP) that exists only in the GDP-bound state. The compounds impaired SOS-catalysed nucleotide exchange, shifted KRAS towards GDP binding, and reduced Raf effector binding, selectively killing G12C-mutant cells. The compounds were weak but demonstrated mechanism.\n\nThis work led directly to ARS-853, ARS-1620 and then sotorasib (approved 2021) and adagrasib (2022), the first KRAS inhibitors, and inspired covalent and non-covalent approaches to other RAS mutants.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1038/nature12796"}],"tags":[],"related":["paper-drug-dosing-conundrum-nejm-2021","kras-roadmap","paper-codebreak-100-sotorasib-kras-g12c-pancreatic-nejm-2023","paper-almoguera-kras-codon-12-pancreatic-cell-1988"],"cancers":["nsclc","colorectal","pancreatic"],"sections":["targeted-therapy","drug-discovery"],"technologies":["kras-inhibitors","kinase-inhibitors"],"targets":["kras"],"drugs":["sotorasib","adagrasib","daraxonrasib"],"companies":[],"institutions":["ucsf"],"pathways":["ras-mapk"],"terms":[],"trials":[],"people":["kevan-shokat"],"bottlenecks":["b-undruggable-targets","b-resistance"],"keyPapers":[],"journals":["nature"],"dependsOn":[],"notes":[],"journal":"Nature","year":2013,"doi":"10.1038/nature12796","pmid":"24256730","authors":"Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM","paperType":"basic","findings":["Identified covalent compounds binding cysteine 12 of KRAS G12C in a cryptic switch-II pocket visible only in the GDP-bound state","Compounds impaired SOS-mediated nucleotide exchange and shifted the nucleotide preference from GTP to GDP","Effector (Raf) binding was decreased and G12C-mutant cell viability selectively reduced","Mutant-specific mechanism: wild-type KRAS was unaffected, giving a therapeutic window"],"whatItMeans":"The most frequently mutated oncogene in cancer stopped being undruggable, and patients with KRAS G12C lung and bowel cancers now have targeted pills. The approach, exploiting a mutation-created chemical handle and an inactive-state pocket, has become a template for other hard targets.","caveats":["The original compounds were micromolar tools, not drugs; a decade of medicinal chemistry was required","Applies only to G12C; other KRAS mutants lack a reactive cysteine, though pan-RAS(ON) inhibitors are now emerging","Clinical responses to G12C inhibitors are shorter than for EGFR or ALK inhibitors, and resistance is rapid","Tumour-type dependence: colorectal G12C cancers respond poorly to monotherapy"],"changedPractice":false},"route":"/key-papers/paper-ostrem-kras-g12c-nature-2013/","neighbours":{"paper":[{"id":"paper-codebreak-100-sotorasib-kras-g12c-pancreatic-nejm-2023","kind":"paper","name":"CodeBreaK 100: sotorasib in KRAS p.G12C-mutated advanced pancreatic cancer","route":"/key-papers/paper-codebreak-100-sotorasib-kras-g12c-pancreatic-nejm-2023/"},{"id":"paper-codebreak-200-lancet-2023","kind":"paper","name":"CodeBreaK 200: sotorasib versus docetaxel in KRAS G12C-mutated lung cancer, a modest win for the first KRAS drug","route":"/key-papers/paper-codebreak-200-lancet-2023/"},{"id":"paper-codebreak-300-nejm-2023","kind":"paper","name":"CodeBreaK 300: sotorasib plus panitumumab in chemotherapy-refractory KRAS G12C colorectal cancer","route":"/key-papers/paper-codebreak-300-nejm-2023/"},{"id":"paper-drug-dosing-conundrum-nejm-2021","kind":"paper","name":"FDA's Project Optimus manifesto: cancer drugs are approved at doses that are too high","route":"/key-papers/paper-drug-dosing-conundrum-nejm-2021/"},{"id":"paper-almoguera-kras-codon-12-pancreatic-cell-1988","kind":"paper","name":"Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes","route":"/key-papers/paper-almoguera-kras-codon-12-pancreatic-cell-1988/"}],"roadmap":[{"id":"kras-roadmap","kind":"roadmap","name":"KRAS roadmap: undruggable → G12C → pan-RAS","route":"/roadmaps/kras-roadmap/"},{"id":"pancreatic-roadmap","kind":"roadmap","name":"Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question","route":"/roadmaps/pancreatic-roadmap/"}],"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"kras-g12c-nsclc","kind":"cancer","name":"KRAS G12C-mutant non-small-cell lung cancer","route":"/cancers/kras-g12c-nsclc/"},{"id":"kras-g12c-pdac","kind":"cancer","name":"KRAS G12C-mutant pancreatic ductal adenocarcinoma","route":"/cancers/kras-g12c-pdac/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"}],"section":[{"id":"drug-discovery","kind":"section","name":"Drug Discovery Platforms","route":"/fronts/drug-discovery/"},{"id":"targeted-therapy","kind":"section","name":"Targeted Therapy","route":"/fronts/targeted-therapy/"}],"technology":[{"id":"kras-inhibitors","kind":"technology","name":"KRAS & RAS inhibitors","route":"/technologies/kras-inhibitors/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"target":[{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"}],"drug":[{"id":"adagrasib","kind":"drug","name":"Adagrasib","route":"/drugs/adagrasib/"},{"id":"daraxonrasib","kind":"drug","name":"Daraxonrasib","route":"/drugs/daraxonrasib/"},{"id":"sotorasib","kind":"drug","name":"Sotorasib","route":"/drugs/sotorasib/"}],"institution":[{"id":"ucsf","kind":"institution","name":"UCSF Helen Diller Family Comprehensive Cancer Center","route":"/institutions/ucsf/"}],"pathway":[{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"}],"person":[{"id":"ferdinandos-skoulidis","kind":"person","name":"Ferdinandos Skoulidis","route":"/people/ferdinandos-skoulidis/"},{"id":"kevan-shokat","kind":"person","name":"Kevan M. Shokat","route":"/people/kevan-shokat/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/"}],"journal":[{"id":"nature","kind":"journal","name":"Nature","route":"/journals/nature/"}]}}