9BFZ

Tri-complex of Compound-5, KRAS G12C, and CypA

This is a non-PDB format compatible entry.

Summary for 9BFZ

• Entry DOI: 10.2210/pdb9bfz/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, tricomplex, signaling protein-inhibitor complex, signaling protein, signaling protein/inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 77883.92

Authors

Tomlinson, A.C.A.,Saldajeno-Concar, M.,Knox, J.E.,Yano, J.K. (deposition date: 2024-04-18, release date: 2025-03-05, Last modification date: 2025-04-09)

Primary citation

Cregg, J.,Pota, K.,Tomlinson, A.C.A.,Yano, J.,Marquez, A.,Liu, Y.,Schulze, C.J.,Seamon, K.J.,Holderfield, M.,Wei, X.,Zhuang, Y.,Yang, Y.C.,Jiang, J.,Huang, Y.,Zhao, R.,Ling, Y.,Wang, Z.,Flagella, M.,Wang, Z.,Singh, M.,Knox, J.E.,Nichols, R.,Wildes, D.,Smith, J.A.M.,Koltun, E.S.,Gill, A.L.
Discovery of Elironrasib (RMC-6291), a Potent and Orally Bioavailable, RAS(ON) G12C-Selective, Covalent Tricomplex Inhibitor for the Treatment of Patients with RAS G12C-Addicted Cancers.
J.Med.Chem., 68:6041-6063, 2025

PubMed Abstract: The discovery of elironrasib (RMC-6291) represents a significant breakthrough in targeting the previously deemed undruggable GTP-bound, active KRAS. To target the active state of RAS (RAS(ON)) directly, we have employed an innovative tri-complex inhibitor (TCI) modality involving formation of a complex with an inhibitor, the intracellular chaperone protein CypA, and the target protein KRAS in its GTP-bound form. The resulting tri-complex inhibits oncogenic signaling, inducing tumor regressions across various preclinical models of KRAS mutant human cancers. Here we report structure-guided medicinal chemistry efforts that led to the discovery of elironrasib, a potent, orally bioavailable, RAS(ON) G12C-selective, covalent, tri-complex inhibitor. The investigational agent elironrasib is currently undergoing phase 1 clinical trials (NCT05462717, NCT06128551, NCT06162221), with preliminary data indicating clinical activity in patients who had progressed on first-generation inactive state-selective KRAS inhibitors.

PubMed: 39993169
DOI: 10.1021/acs.jmedchem.4c02313

Experimental method

X-RAY DIFFRACTION (1.8 Å)