# Covalent chemistry for the RAS mutations that still have no drug

Source: https://onco.cc/ideas/idea-bio1-pan-ras-covalent-g12d/  
OnCo record `idea-bio1-pan-ras-covalent-g12d` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- 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.
- Proposed 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

## Sources

- Bottleneck evidence (The undruggable drivers): Dang et al., Drugging the 'undruggable' cancer targets (Nature Reviews Cancer 2017): https://doi.org/10.1038/nrc.2017.36

## Connected records

- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Metastatic pancreatic ductal adenocarcinoma](https://onco.cc/cancers/metastatic-pdac/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/)
- technologies: [KRAS & RAS inhibitors](https://onco.cc/technologies/kras-inhibitors/)
- targets: [KRAS](https://onco.cc/targets/kras/)
- drugs: [Adagrasib](https://onco.cc/drugs/adagrasib/), [Daraxonrasib](https://onco.cc/drugs/daraxonrasib/), [Sotorasib](https://onco.cc/drugs/sotorasib/)
- companies: [Frontier Medicines](https://onco.cc/companies/frontier-medicines/), [Quanta Therapeutics](https://onco.cc/companies/quanta-therapeutics/), [Revolution Medicines](https://onco.cc/companies/revolution-medicines/)
- trials: [CodeBreaK 300](https://onco.cc/trials/codebreak-300/), [RASolute 302](https://onco.cc/trials/rasolute-302/), [Study of Daraxonrasib (RMC-6236) in Patients With Resected Pancreatic Ductal Adenocarcinoma (PDAC)](https://onco.cc/trials/nct07252232/), [Study of Daraxonrasib and Daraxonrasib + GnP as First-line Treatment in Patients With Metastatic Pancreatic Adenocarcinoma](https://onco.cc/trials/nct07491445/), [Study of Zoldonrasib + Chemo of Investigator's Choice vs Placebo + Chemo of Investigator's Choice as First-line Treatment in Metastatic KRAS G12D-muta](https://onco.cc/trials/nct07621718/)
- bottlenecks: [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/)
- key papers: [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](https://onco.cc/key-papers/paper-kras-colorectal-j-clin-oncol-2011/), [Drugging the 'undruggable' cancer targets](https://onco.cc/key-papers/paper-dang-nat-rev-cancer/), [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](https://onco.cc/key-papers/paper-kras-colorectal-j-clin-oncol-2010/), [Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer](https://onco.cc/key-papers/paper-kras-colorectal-j-clin-oncol-2008/)

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