9BG2

Tri-complex of Compound-10, KRAS G12V, and CypA

This is a non-PDB format compatible entry.

Summary for 9BG2

• Entry DOI: 10.2210/pdb9bg2/pdb
• Descriptor: GTPase KRas, Peptidyl-prolyl cis-trans isomerase A, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (6 entities in total)
• Functional Keywords: inhibitor, complex, small gtpase, cancer, tri-complex, signaling protein-inhibitor complex, signaling protein, signaling protein/inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 77567.80

Authors

Tomlinson, A.C.A.,Bieder, R.,Chen, A.,Knox, J.E.,Yano, J.K. (deposition date: 2024-04-18, release date: 2025-03-19)

Primary citation

Cregg, J.,Edwards, A.V.,Chang, S.,Lee, B.J.,Knox, J.E.,Tomlinson, A.C.A.,Marquez, A.,Liu, Y.,Freilich, R.,Aay, N.,Wang, Y.,Jiang, L.,Jiang, J.,Wang, Z.,Flagella, M.,Wildes, D.,Smith, J.A.M.,Singh, M.,Wang, Z.,Gill, A.L.,Koltun, E.S.
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

PubMed 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).

PubMed: 40056080
DOI: 10.1021/acs.jmedchem.4c02314

Experimental method

X-RAY DIFFRACTION (1.64 Å)