Daraxonrasib

Last updated

Daraxonrasib
Daraxonrasib2.svg
Clinical data
Other namesRMC-6236
Identifiers
  • trans-(1S,2S)-N-[(7S,13S)-21-ethyl-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.12,5.19,13.022,26]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methylcyclopropane-1-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
Chemical and physical data
Formula C44H58N8O5S
Molar mass 811.06 g·mol−1
3D model (JSmol)
  • CCN1C2=C3C=C(C=C2)C4=CSC(=N4)C[C@@H](C(=O)N5CCC[C@H](N5)C(=O)OCC(CC3=C1C6=C(N=CC(=C6)N7CCN(CC7)C)[C@H](C)OC)(C)C)NC(=O)[C@H]8C[C@@H]8C
  • InChI=InChI=1S/C44H58N8O5S/c1-8-51-37-12-11-28-19-31(37)33(40(51)32-20-29(23-45-39(32)27(3)56-7)50-16-14-49(6)15-17-50)22-44(4,5)25-57-43(55)34-10-9-13-52(48-34)42(54)35(21-38-46-36(28)24-58-38)47-41(53)30-18-26(30)2/h11-12,19-20,23-24,26-27,30,34-35,48H,8-10,13-18,21-22,25H2,1-7H3,(H,47,53)/t26-,27-,30-,34-,35-/m0/s1
  • Key:FVICRBSEYSHKFY-JYQNNKODSA-N

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

  1. ↑ Cregg J, Edwards AV, Chang S, Lee BJ, Knox JE, Tomlinson AC, et al. (March 2025). "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. doi:10.1021/acs.jmedchem.4c02314. PMID   40056080.
  2. ↑ Sava J (July 1, 2025). "Daraxonrasib Earns FDA Breakthrough Status in Pancreatic Cancer". Targeted Oncology. Retrieved October 12, 2025.
  3. ↑ Jiang J, Jiang L, Maldonato BJ, Wang Y, Holderfield M, Aronchik I, et al. (June 2024). "Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers". Cancer Discovery. 14 (6): 994–1017. doi:10.1158/2159-8290.CD-24-0027. PMC   11149917 . PMID   38593348.
  4. ↑ 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.
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