Daraxonrasib (RMC-6236) Receives FDA Approval for Metastatic Pancreatic Cancer
The FDA approved daraxonrasib, an oral RAS(ON) multi-selective inhibitor from Revolution Medicines, on August 26, 2026 for previously treated metastatic pancreatic ductal adenocarcinoma (PDAC).¹ The drug had Breakthrough Therapy and Orphan Drug designations and Priority Review. The approval rests on the Phase 3 RASolute 302 trial (NCT06625320).² In patients with RAS G12-mutant PDAC, the primary analysis population, median overall survival was 13.2 months with daraxonrasib and 6.6 months with the investigator's choice of chemotherapy.
Figure 1 Chemical structure of daraxonrasib (RMC-6236), a macrocyclic pan-RAS(ON) inhibitor.
How daraxonrasib inhibits RAS: mechanism of action
RAS proteins drive more than 90% of pancreatic cancers. Until recently, the ligand-binding surface of active, GTP-bound RAS was considered undruggable.³ The two approved targeted agents, sotorasib and adagrasib, address only the KRASG12C subset (roughly one in seven RAS-driven tumours) and bind the inactive GDP-bound state.
Daraxonrasib works differently. It first forms a binary complex with cyclophilin A (CypA). That complex creates a composite binding pocket, then recruits GTP-bound RAS and blocks effector binding to RAF. The binding surface is conserved across mutant and wild-type KRAS, NRAS and HRAS, so one molecule covers all three isoforms.
Synthesis of Daraxonrasib: ChemAIRS® Retrosynthetic Analysis
ChemAIRS® was used to perform retrosynthetic analysis of daraxonrasib in two complementary modes: one biased toward discovery-stage practicality, the other toward scale-up considerations. Daraxonrasib is a beyond-rule-of-five macrocycle (MW 811). ³ Four features make it a demanding scale target:
A thiazole core and several other heterocycles.
A chiral piperazic acid built into the macrolactone.
A trans-methylcyclopropyl amide.
An atropisomeric indole–pyridine biaryl linkage.
The dense stereochemistry and the macrocyclization step are what a route has to handle well, whether the goal is milligrams for discovery or kilograms for development.
How ChemAIRS® Handled the Daraxonrasib Synthesis
ChemAIRS® reconstructed two viable routes to the stereochemically enriched bRo5 macrocycle, combining literature and patent precedent with algorithm-designed chemistry where precedent was unavailable.
The Retrosynthesis module identified an 8-step LLS route from multiple sources. Manual disconnection of two costly building blocks expanded the route to 17 steps (13-step LLS), while identifying raw materials priced below $60/g. The Process Chemistry module generated a 32-step route with an 18-step LLS, using kilo-scale building blocks and three algorithm-designed transformations, including one directly enabling the final alkylation reaction.
Daraxonrasib synthesis, Route 1: Retrosynthesis module with cost-controlled building blocks
The ChemAIRS® Retrosynthesis module returned a fully linear route with an 8-step longest linear sequence (LLS). It draws on three patents⁴⁻⁶ and ends with the HATU-mediated amide coupling reported by Cregg and coworkers.³ The module takes known chemistry from whichever source has the best precedent, instead of copying one reported sequence or building a fully algorithmic route.
Scheme 1 ChemAIRS retrosynthesis of daraxonrasib: known 8-step route from three patents.
Two building blocks near the start of that route, 2a and especially 1b, cost too much for many discovery programs. We disconnected both manually inside the platform. The new raw materials can all be bought for under $60 per gram, at the price of nine added known reactions. The extended route has 17 total steps and a 13-step LLS.
Scheme 2 ChemAIRS® proposes extended 17-step route to daraxonrasib (RMC-6236), with all raw materials available under $60 per gram.
Two points follow from this result:
Chemical.AI's vendor network supplies advanced building blocks, so a chemist can start from the best strategy without first checking that the starting materials exist.
The manual disconnection is done in the same interface (Schemes 3 and 4). That lowers project cost and shortens route design time.
Scheme 3 ChemAIRS generates a convergent route to daraxonrasib intermediate 11a from a manual disconnection.
Scheme 4 ChemAIRS builds a five-step route to daraxonrasib intermediate 6b from a manual disconnection.
Daraxonrasib synthesis, Route 2: Process Chemistry module with algorithm-designed final-stage steps
The ChemAIRS® Process Chemistry module returned a longer, more convergent route. It is based mostly on known chemistry, with several algorithm-designed steps in the final stages (Scheme 5). The route has 32 total steps and an 18-step LLS. All building blocks are known to be available in kilogram quantities, and many of the reactions have been described on larger scale. Most reactions without direct large-scale precedent have at least one analogous transformation reported at 100 g scale or greater, or in Organic Process Research & Development.
Scheme 5. ChemAIRS-guided Process Chemistry route to daraxonrasib (RMC-6236): the final stages.
Key transformations in the process route
Buchwald–Hartwig amination (intermediate 31a). Intermediate 31a is known, but it has not been made by the proposed Buchwald–Hartwig amination of N-methylpiperazine (30a) with the 3-iodopyridine derivative 30b (Scheme 6). The path to 30b starts with a 120 g asymmetric transfer hydrogenation of 26a to give 27a,⁷ followed by a 405 kg O-methylation to give 28a.⁸
Scheme 6 ChemAIRS-designed Process Chemistry route to daraxonrasib (RMC-6236): preparation of intermediate 31a
Chiral cyclopropane and macrolactonization (intermediate 31b). This route installs the chiral cyclopropanecarboxylic acid derivative 24a, which can come from ozonolysis of the aryl precursor 23a (Scheme 7).⁹ The same section closes the macrocycle (21a) by lactonization under mild conditions.¹⁰
Scheme 7 ChemAIRS-designed Process Chemistry route to daraxonrasib (RMC-6236): preparation of intermediate 31b with a chiral cyclopropanecarboxylic acid and macrolactonization
Asymmetric electrophilic hydrazination (piperazic acid fragment). Fragment 18a, a precursor to 19a, is made from oxazolidinone 13a and carboxylic acid 13b. The key step sets the stereochemistry needed for protected piperazic acid 16a (Scheme 8).¹¹
Fragment 18b. The more complex fragment 18b is assembled in 12 known steps, which contribute 10 steps to the total LLS (Scheme 9). One open question for scale-up: carrying the TBDPS protecting group through, instead of replacing it with an acyl group (the overall 5a to 7a transformation), would save two steps. Whether that works depends on how easy the protected intermediate is to handle and purify at larger scale.
Scheme 8 ChemAIRS-designed Process Chemistry route to daraxonrasib (RMC-6236): five-step synthesis of piperazic acid ester intermediate 18a
Scheme 9 ChemAIRS-designed Process Chemistry route to daraxonrasib (RMC-6236): twelve-step synthesis of key intermediate 18b
ChemAIRS®: Computer-Aided Synthesis Planning for Chemistry Researchers
ChemAIRS® is a computer-aided synthesis planning (CASP) platform that proposes retrosynthetic routes to known and novel molecules, ranking them by feasibility and by access to readily available building blocks. Its Retrosynthesis module combines machine learning with encoded chemical logic, and every step can be interrogated. Chemists can therefore troubleshoot a disconnection or explore alternative methodology, rather than accept a route as given. The platform is intended to support the chemist's strategic decisions, not to make them.
References
FDA approves first in class targeted therapy for metastatic pancreatic cancer. News release. US Food and Drug Administration. August 26, 2026. Accessed September 1, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-class-targeted-therapy-metastatic-pancreatic-cancer
O'Reilly EM, Wainberg ZA, Hendifar AE, et al; RASolute 302 Trial Investigators. Daraxonrasib or chemotherapy in previously treated metastatic pancreatic cancer. N Engl J Med. 2026;395(4):325-337. https://doi.org/10.1056/NEJMoa2605555
Cregg J, Edwards AV, Chang S, et al. Discovery of daraxonrasib (RMC-6236), a potent and orally bioavailable RAS(ON) multi-selective, noncovalent tri-complex inhibitor for the treatment of patients with multiple RAS-addicted cancers. J Med Chem. 2025;68(6):6064-6083. https://doi.org/10.1021/acs.jmedchem.4c02314
Aggen J, Burnett GL, Pitzen J, et al., inventors; Revolution Medicines, Inc., applicant. RAS Inhibitors. US patent 20210130326A1. May 6, 2021.
Koltun ES, Cregg J, Aay N, et al., inventors; Revolution Medicines, Inc., applicant. RAS Inhibitors. US patent 0130369A1. May 6, 2021.
Buckl A, Burnett GL, Cregg J, et al., inventors; Revolution Medicines, Inc., applicant. RAS Inhibitors. WIPO patent WO2023060253A1. April 13, 2023.
Knox JE, Koltun ES, Liu J, et al., inventors; Revolution Medicines, Inc., applicant. RAS Inhibitors. US patent 0154171A1. May 15, 2025.
Li S, Yi L, Liu J, Lobben P, Wang R, Ballmer S, Huang X, inventors; Revolution Medicines, Inc., applicant. Synthesis of RAS Inhibitors. WIPO patent WO2024216008A1. October 17, 2024.
Baldwin JE, Carter CG. Complete Kinetic Analysis of the Thermal Stereomutations of (+)-(1S,2S,3R)-r-1-Cyano-t-2-methyl-1,2,t-3-trideuteriocyclopropane. J. Am. Chem. Soc. 1982;104(5):1362-1368. https://doi.org/10.1021/ja00369a036
Wu W, Ding L, Li S, et al., inventors; Betta Pharmaceuticals Co., Ltd., applicant. Pan-KRAS Inhibitor and Use Thereof in Medicines. WIPO patent WO2025087431A1. May 1, 2025.
Hale KJ, Cai J, Delisser V, et al; Enantioselective Synthesis of (3R)- and (3S)-Piperazic Acids. The Comparative Unimportance of DMPU Mediated Retro-Hydrazination. Tetrahedron. 1996;52(3):1047-1068. https://doi.org/10.1016/0040-4020(95)00938-8