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 Mar 27;68(6):6064-6083. doi: 10.1021/acs.jmedchem.4c02314.
James Cregg  1 ,  Anne V Edwards  1 ,  Stephanie Chang  1 ,  Bianca J Lee  1 ,  John E Knox  1 ,  Aidan C A Tomlinson  1 ,  Abby Marquez  1 ,  Yang Liu  1 ,  Rebecca Freilich  1 ,  Naing Aay  1 ,  Yingyun Wang  1 ,  Lingyan Jiang  1 ,  Jingjing Jiang  1 ,  Zhican Wang  1 ,  Michael Flagella  1 ,  David Wildes  1 ,  Jacqueline A M Smith  1 ,  Mallika Singh  1 ,  Zhengping Wang  1 ,  Adrian L Gill  1 ,  Elena S Koltun  1
Affiliations
  • 1. Revolution Medicines, Inc., Redwood City, California 94063, United States.
PMID: 40056080 DOI: 10.1021/acs.jmedchem.4c02314
Abstract

Oncogenic Ras mutations are among the most common in human cancers. To target the active, GTP-bound state of Ras(ON) directly, we employed an innovative tri-complex inhibitor (TCI) modality. Formation of a complex with an intracellular chaperone protein CypA, an inhibitor, and a target protein Ras blocks effector binding, inhibiting downstream Ras signaling and tumor cell proliferation. Herein, we describe the structure-guided SAR journey that led to the discovery of daraxonrasib (RMC-6236), a noncovalent, potent tri-complex inhibitor of multiple Ras mutant and wild-type (WT) variants. This orally bioavailable bRo5 macrocyclic molecule occupies a unique composite binding pocket comprising CypA and SWI/SWII regions of Ras(ON). To achieve broad-spectrum Ras isoform activity, we deployed an SAR campaign that focused on interactions with residues conserved between mutants and WT Ras isoforms. Concurrent optimization of potency and drug-like properties led to the discovery of daraxonrasib (RMC-6236), currently in clinical evaluation in Ras mutant advanced solid Tumors (NCT05379985; NCT06040541; NCT06162221; NCT06445062; NCT06128551).