Chemistry:Daraxonrasib
Daraxonrasib (RMC-6236) is an investigational new drug being evaluated by Revolution Medicines to treat advanced solid tumors with RAS mutations, especially metastatic pancreatic ductal adenocarcinoma (PDAC) containing KRAS G12X mutations.[1] It has received a breakthrough therapy designation from the U.S. Food and Drug Administration.[2]
Daraxonrasib is an orally active, multi-selective RAS inhibitor that uses a novel tri-complex mechanism to target the active, GTP-bound form of RAS proteins, including mutant and wild-type types. Unlike conventional RAS inhibitors, it first binds to the chaperone-like protein cyclophilin A to form a complex, which then attaches to active RAS. This interaction blocks downstream effector binding and inhibits oncogenic signaling.[3]
As of 2025, Daraxonrasib clinical trial is in phase 3 to assess efficacy compared to current standard-of-care chemotherapy.[4]
References
- ↑ "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". Journal of Medicinal Chemistry 68 (6): 6064–6083. March 2025. doi:10.1021/acs.jmedchem.4c02314. PMID 40056080.
- ↑ "Daraxonrasib Earns FDA Breakthrough Status in Pancreatic Cancer". July 1, 2025. https://www.targetedonc.com/view/daraxonrasib-earns-fda-breakthrough-status-in-pancreatic-cancer.
- ↑ "Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers". Cancer Discovery 14 (6): 994–1017. June 2024. doi:10.1158/2159-8290.CD-24-0027. PMID 38593348.
- ↑ Revolution Medicines, Inc. (2024-11-12). A Multicenter Open-Label Study of RMC-6236 in Patients With Advanced Solid Tumors Harboring Specific Mutations in RAS (Report). clinicaltrials.gov. https://clinicaltrials.gov/study/NCT05379985.
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