RAS is the most frequently mutated oncogene family in human cancer, yet for decades it was considered “undruggable.” The arrival of mutant-selective KRAS G12C inhibitors changed that narrative for a narrow slice of patients, but the majority of RAS-driven tumors—those harboring G12D, G12V, G12R, G13X, or Q61X alterations, or amplified wild-type RAS—remained without a direct, broadly active inhibitor. RMC-6236 (daraxonrasib) is one of the most studied molecules attempting to close that gap, and it has become a reference tool compound for laboratories investigating active-state RAS pharmacology.

This article summarizes what RMC-6236 is, how its tri-complex mechanism works, the biology that makes it distinctive, and the research contexts in which the compound is used. RMC-6236 is supplied by Biofargo as a research-grade material for research use only.

What is RMC-6236?

RMC-6236 (daraxonrasib; CAS 2765081-21-6) is an orally bioavailable, noncovalent, RAS(ON) multi-selective tri-complex inhibitor developed by Revolution Medicines. Chemically, it is a beyond-Rule-of-Five (bRo5) macrocycle engineered to engage a composite binding surface formed between RAS and an intracellular chaperone protein.

Unlike inhibitors that target the inactive, GDP-bound RAS(OFF) state, RMC-6236 targets the active, GTP-bound RAS(ON) state—the conformation that actually drives downstream signaling. And unlike single-mutant covalent agents, it is multi-selective: it engages a range of mutant RAS variants as well as wild-type RAS, which is why it is frequently described as a “pan-RAS(ON)” inhibitor.

Mechanism of action: a molecular glue that builds a tri-complex

The defining feature of RMC-6236 is its tri-complex (molecular glue) mechanism:

1. RMC-6236 first binds the ubiquitously expressed chaperone cyclophilin A (CypA).

2. The RMC-6236–CypA pair then recruits active, GTP-bound RAS, occupying a composite pocket spanning CypA and the switch I/switch II (SWI/SWII) regions of RAS.

3. The resulting RAS : RMC-6236 : CypA tri-complex sterically blocks RAS from engaging its downstream effectors—RAF and PI3K—thereby shutting down MAPK (RAF–MEK–ERK) signaling and suppressing RAS-driven proliferation.

Because the inhibitor anchors on residues conserved across RAS isoforms and mutants, it achieves broad-spectrum activity rather than single-codon selectivity. Reported in vitro binding affinities illustrate this breadth, with dissociation constants in the high-nanomolar range across multiple variants (for example, KRAS G12V ≈ 131 nM, KRAS G12D ≈ 364 nM, and wild-type KRAS ≈ 154 nM). In RAS-driven cell lines, the compound suppresses phospho-ERK signaling and clonogenic survival; in xenograft models, oral dosing has produced dose-dependent, durable tumor regressions accompanied by suppression of RAS-pathway biomarkers.

Why the “active-state, multi-selective” design matters

More than 90% of pancreatic ductal adenocarcinomas and roughly 30% of non–small cell lung cancers carry an oncogenic RAS alteration, spread across many different codons. A single-mutant approach addresses only a fraction of these tumors. By targeting the shared active conformation, RMC-6236 offers a single pharmacological tool for interrogating RAS dependency across:

- KRAS, NRAS, and HRAS isoforms

- G12X, G13X, and Q61X mutant classes

- Wild-type RAS in contexts of pathway amplification or upstream activation

This makes it valuable not only as a clinical candidate but as a laboratory probe for dissecting RAS biology that previously had no direct chemical handle.

Clinical context for the research community

RMC-6236 is the subject of an extensive clinical program in RAS-addicted solid tumors. The most discussed dataset comes from the Phase 3 RASolute 302 trial, which compared once-daily oral RMC-6236 (300 mg) against investigator’s choice of standard cytotoxic chemotherapy in patients with previously treated metastatic pancreatic ductal adenocarcinoma.

In that randomized trial of roughly 500 patients, RMC-6236 produced a median overall survival of 13.2 months versus 6.7 months for chemotherapy (hazard ratio 0.40), corresponding to a 60% reduction in the risk of death, with a parallel progression-free survival benefit. Notably, the survival advantage was observed across the intent-to-treat population—patients with RAS G12 mutations and those with wild-type RAS alike—and the trial met its primary and key secondary endpoints, including objective response rate and patient-reported quality of life. Earlier Phase 1 work in RAS-mutant NSCLC reported an objective response rate of approximately 38% in previously treated patients harboring RAS G12X mutations.

Research applications

As a well-characterized, mechanistically distinct chemical probe, RMC-6236 is used in basic and translational research, including:

- RAS pathway and MAPK signaling studies — interrogating RAS(ON)-dependent ERK signaling in mutant and wild-type backgrounds.

- Tri-complex / molecular-glue pharmacology — studying CypA-dependent ternary complex formation as a modality.

- Resistance mechanism research — for example, probing how SWI/SWII pocket mutations (such as Y64 substitutions) alter tri-complex assembly and drug sensitivity.

- Pharmacodynamic and ctDNA studies — correlating RAS variant allele frequency changes with pathway inhibition.

- Combination studies — pairing active-state RAS inhibition with upstream/downstream or parallel-pathway agents.

- Comparator / reference standard — benchmarking next-generation RAS-targeting chemotypes in screening cascades and structural biology.

Reported potency

In preclinical PDAC models, reported half-maximal inhibitory concentration (IC50) values for RMC-6236 fall in the 20–40 nM range across mouse and human pancreatic ductal adenocarcinoma. In the SUIT-2 pancreatic cancer cell line, an IC50 of approximately 2.02 nM has been reported. These values reflect the compound’s activity against RAS(ON)-dependent signaling in RAS-addicted backgrounds.

Product specifications

Biofargo supplies RMC-6236 (daraxonrasib) as a research-grade compound.

For current pricing, available pack sizes, MSDS, and bulk inquiries, visit the RMC-6236 product page on biofargo.com or contact our team at contact@biofargo.com. Bulk and recurring-order discounts are available for academic and industry laboratories.

References

1. Jiang J, et al. Discovery of Daraxonrasib (RMC-6236), a Potent and Orally Bioavailable RAS(ON) Multi-selective, Noncovalent Tri-complex Inhibitor. J. Med. Chem. 2025; 68(6): 6064–6083.

2. RASolute 302 (NCT06625320): A Phase 3 randomized study of daraxonrasib (RMC-6236) versus standard-of-care therapy in previously treated metastatic PDAC.

3. Revolution Medicines clinical and corporate disclosures regarding daraxonrasib (RMC-6236).

Content for scientific and educational purposes. RMC-6236 sold by Biofargo is for research use only.