{"entity":{"id":"idea-bio1-pan-ras-covalent-g12d","kind":"idea","name":"Covalent chemistry for the RAS mutations that still have no drug","aka":[],"tldr":"One RAS mutation can now be drugged because it offers a reactive handle. Most RAS mutations do not, so new chemistry is needed to grab other amino acids.","summary":"KRAS G12C inhibitors work by covalently modifying a cysteine. G12D, G12V and G13D, which together account for most RAS-driven cancer, lack that cysteine. Aspartate-targeting and lysine-targeting covalent chemistries, non-covalent tri-complex RAS(ON) inhibitors and pan-RAS agents are all in early clinical development. The proposal is a focused public-private chemistry programme on non-cysteine covalent warheads with tolerable reactivity, plus open sharing of failed warhead chemotypes.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (The undruggable drivers): Dang et al., Drugging the 'undruggable' cancer targets (Nature Reviews Cancer 2017)","url":"https://doi.org/10.1038/nrc.2017.36"}],"tags":[],"related":[],"cancers":["pancreatic","colorectal"],"sections":[],"technologies":["kras-inhibitors"],"targets":["kras"],"drugs":["sotorasib","adagrasib","daraxonrasib"],"companies":["revolution-medicines","frontier-medicines","quanta-therapeutics"],"institutions":[],"pathways":[],"terms":[],"trials":["codebreak-300","nct07252232","nct07491445","nct07621718","rasolute-302"],"people":[],"bottlenecks":["b-undruggable-targets"],"keyPapers":["paper-dang-nat-rev-cancer","paper-kras-colorectal-j-clin-oncol-2008","paper-kras-colorectal-j-clin-oncol-2011","paper-kras-colorectal-j-clin-oncol-2010"],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"A non-cysteine covalent warhead class can achieve selective, durable engagement of KRAS G12D in vivo with acceptable off-target proteome reactivity, giving deeper responses than reversible binders.","rationale":"Covalency solves the picomolar-affinity requirement created by RAS's high GTP affinity; the G12C precedent shows that irreversible engagement translates into clinical activity.","test":"Chemoproteomic profiling of candidate warheads across the reactive proteome, then in vivo pharmacodynamics in KRAS G12D pancreatic and colorectal models against a benchmark RAS(ON) inhibitor.","maturity":"early-clinical","actor":"industry","cost":"large","horizonYears":5},"route":"/ideas/idea-bio1-pan-ras-covalent-g12d/","neighbours":{"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"metastatic-pdac","kind":"cancer","name":"Metastatic pancreatic ductal adenocarcinoma","route":"/cancers/metastatic-pdac/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"}],"technology":[{"id":"kras-inhibitors","kind":"technology","name":"KRAS & RAS inhibitors","route":"/technologies/kras-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/"}],"company":[{"id":"frontier-medicines","kind":"company","name":"Frontier Medicines","route":"/companies/frontier-medicines/"},{"id":"quanta-therapeutics","kind":"company","name":"Quanta Therapeutics","route":"/companies/quanta-therapeutics/"},{"id":"revolution-medicines","kind":"company","name":"Revolution Medicines","route":"/companies/revolution-medicines/"}],"trial":[{"id":"codebreak-300","kind":"trial","name":"CodeBreaK 300","route":"/trials/codebreak-300/"},{"id":"rasolute-302","kind":"trial","name":"RASolute 302","route":"/trials/rasolute-302/"},{"id":"nct07252232","kind":"trial","name":"Study of Daraxonrasib (RMC-6236) in Patients With Resected Pancreatic Ductal Adenocarcinoma (PDAC)","route":"/trials/nct07252232/"},{"id":"nct07491445","kind":"trial","name":"Study of Daraxonrasib and Daraxonrasib + GnP as First-line Treatment in Patients With Metastatic Pancreatic Adenocarcinoma","route":"/trials/nct07491445/"},{"id":"nct07621718","kind":"trial","name":"Study of Zoldonrasib + Chemo of Investigator's Choice vs Placebo + Chemo of Investigator's Choice as First-line Treatment in Metastatic KRAS G12D-muta","route":"/trials/nct07621718/"}],"bottleneck":[{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/"}],"paper":[{"id":"paper-kras-colorectal-j-clin-oncol-2011","kind":"paper","name":"Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status","route":"/key-papers/paper-kras-colorectal-j-clin-oncol-2011/"},{"id":"paper-dang-nat-rev-cancer","kind":"paper","name":"Drugging the 'undruggable' cancer targets","route":"/key-papers/paper-dang-nat-rev-cancer/"},{"id":"paper-kras-colorectal-j-clin-oncol-2010","kind":"paper","name":"Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial","route":"/key-papers/paper-kras-colorectal-j-clin-oncol-2010/"},{"id":"paper-kras-colorectal-j-clin-oncol-2008","kind":"paper","name":"Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer","route":"/key-papers/paper-kras-colorectal-j-clin-oncol-2008/"}]}}