9AX6

Tricomplex of RMC-6236, KRAS G12D, and CypA

This is a non-PDB format compatible entry.

Summary for 9AX6

• Entry DOI: 10.2210/pdb9ax6/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/inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 77751.78

Authors

Tomlinson, A.C.A.,Saldajeno-Concar, M.,Knox, J.E.,Yano, J.K. (deposition date: 2024-03-05, release date: 2024-04-17, Last modification date: 2024-06-12)

Primary citation

Jiang, J.,Jiang, L.,Maldonato, B.J.,Wang, Y.,Holderfield, M.,Aronchik, I.,Winters, I.P.,Salman, Z.,Blaj, C.,Menard, M.,Brodbeck, J.,Chen, Z.,Wei, X.,Rosen, M.J.,Gindin, Y.,Lee, B.J.,Evans, J.W.,Chang, S.,Wang, Z.,Seamon, K.J.,Parsons, D.,Cregg, J.,Marquez, A.,Tomlinson, A.C.A.,Yano, J.K.,Knox, J.E.,Quintana, E.,Aguirre, A.J.,Arbour, K.C.,Reed, A.,Gustafson, W.C.,Gill, A.L.,Koltun, E.S.,Wildes, D.,Smith, J.A.M.,Wang, Z.,Singh, M.
Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers.
Cancer Discov, 14:994-1017, 2024

PubMed Abstract: RAS-driven cancers comprise up to 30% of human cancers. RMC-6236 is a RAS(ON) multi-selective noncovalent inhibitor of the active, GTP-bound state of both mutant and wild-type variants of canonical RAS isoforms with broad therapeutic potential for the aforementioned unmet medical need. RMC-6236 exhibited potent anticancer activity across RAS-addicted cell lines, particularly those harboring mutations at codon 12 of KRAS. Notably, oral administration of RMC-6236 was tolerated in vivo and drove profound tumor regressions across multiple tumor types in a mouse clinical trial with KRASG12X xenograft models. Translational PK/efficacy and PK/PD modeling predicted that daily doses of 100 mg and 300 mg would achieve tumor control and objective responses, respectively, in patients with RAS-driven tumors. Consistent with this, we describe here objective responses in two patients (at 300 mg daily) with advanced KRASG12X lung and pancreatic adenocarcinoma, respectively, demonstrating the initial activity of RMC-6236 in an ongoing phase I/Ib clinical trial (NCT05379985).

PubMed: 38593348
DOI: 10.1158/2159-8290.CD-24-0027

Experimental method

X-RAY DIFFRACTION (1.65 Å)