KRAS G12V: the common mutation still without a drug

KRAS G12V is one of the most common oncogenic mutations in human cancer, yet it is the awkward middle child of the KRAS family: G12C has two approved inhibitors, G12D has a clutch of clinical-stage candidates, and G12V has neither. The reason is partly chemical and partly historical, and it explains why the field has pivoted from allele-specific design toward pan-RAS strategies.

Why G12C got drugged first

Glycine 12 sits at the lip of the nucleotide pocket in KRAS, right where GTP hydrolysis happens. Mutating it to almost anything impairs the intrinsic hydrolysis that would otherwise switch the protein off, so the mutant stays locked in its active, GTP-bound, signaling state. G12V impairs intrinsic hydrolysis roughly 9-fold, which is among the most potent shut-offs of the off-switch in the G12 series.

The breakthrough for G12C was not that the cysteine made the protein more druggable in general. It was that the mutant cysteine provides a nucleophilic handle a covalent warhead can lock onto, in a transient pocket (the switch-II pocket) that only opens in the GDP-bound state. Sotorasib and adagrasib were built around that cysteine. Valine has no such handle. It is small, hydrophobic, and chemically inert, so the entire covalent playbook that cracked G12C simply does not transfer.

The undruggable-surface problem

Beyond the missing warhead anchor, KRAS itself is a famously hard target. Its surface is comparatively smooth and the only deep, well-defined cavity is the picomolar-affinity nucleotide pocket already occupied by GTP. Competing with cellular GTP for that site is a non-starter. The switch-I and switch-II regions that mediate effector binding are shallow and polar, the kind of interface that looks undruggable to a classic small-molecule docking campaign. For G12V you do not even get the consolation of a covalent foothold.

The allele-specific attempts

A few programs are still chasing G12V directly:

• JAB-23000 — an allele-selective KRAS G12V inhibitor in early development. Allele selectivity is the holy grail here because it spares wild-type RAS in normal tissue, which should widen the therapeutic window.
• MRTX1133 — designed as a non-covalent G12D inhibitor, but preclinical data suggest its binding mode may extend to G12V, since neither relies on a covalent bond. It is a useful proof that you can get potent, selective binding to a non-cysteine G12 mutant without a warhead.

The honest status as of 2026: no approved therapy is indicated for KRAS G12V, and most allele-specific G12V candidates are preclinical or in first-in-human dose finding.

The pan-RAS pivot

Because chasing each allele one at a time is slow, much of the energy has moved to inhibitors that hit a broad range of KRAS mutants at once, G12V included:

• BI-2865 — a non-covalent, inactive-state (GDP-bound) selective pan-KRAS inhibitor that binds wild-type and G12A/C/D/V/S, G13 and other mutants with nanomolar affinity, while largely sparing the related NRAS and HRAS. It was reported with atomic-resolution crystal structures showing how a single pharmacophore can engage many different residue-12 substitutions.
• Daraxonrasib (RMC-6236) — a first-in-class oral pan-RAS(ON) inhibitor that works by a molecular-glue mechanism: it recruits the abundant chaperone cyclophilin A to form a tri-complex that clamps the active, GTP-bound RAS and blocks effector engagement. Because it targets the active state by a glue rather than a covalent bond, it covers G12V/D/A/S, G13 and Q61 variants. It is in late-stage trials in RAS-mutant pancreatic cancer.

The trade-off is selectivity. A drug that hits every RAS allele also hits wild-type RAS in healthy cells, so the therapeutic window depends on tumors being more addicted to RAS signaling than normal tissue. That is the central bet of the pan-RAS class, and the clinical data so far suggest the window is real but narrow.

What this means for your docking workflow

G12V is a good stress test for a docking pipeline precisely because there is no covalent shortcut. When you dock a non-covalent candidate against KRAS G12V, the question is whether the pose engages the inactive-state switch-II pocket and whether the valine substitution shifts the score relative to wild-type. As with the EGFR resistance series, the number to watch is the ΔΔ between wild-type KRAS and the G12V mutant, not any single absolute score. A pan-KRAS candidate should show a small, consistent gap across several alleles rather than one spectacular score against one of them.

Try the docking yourself

Open Studio and pick KRAS from the target catalog, then select the G12V mutation chip. Dock a pan-RAS candidate against wild-type, G12C, G12D and G12V together and compare the poses: the inactive-state binders should land in the switch-II pocket across alleles, while a G12C-specific covalent design will only make sense against the cysteine. Liganx puts molecular docking online and free in the browser, so running molecular docking across the whole KRAS allele series takes a few clicks.

Primary sources

• Kim D, et al. Pan-KRAS inhibitor disables oncogenic signalling and tumour growth. Nature 619, 160–166 (2023). doi:10.1038/s41586-023-06123-3
• Ma X, et al. Discovery of daraxonrasib (RMC-6236), a potent and orally bioavailable RAS(ON) multi-selective, noncovalent tri-complex inhibitor. J Med Chem (2024). doi:10.1021/acs.jmedchem.4c02314
• Lu S, et al. The structural basis of oncogenic mutations G12, G13 and Q61 in small GTPase K-Ras4B. Sci Rep 6, 21949 (2016). doi:10.1038/srep21949