8TBG

Tricomplex of RMC-7977, HRAS WT, and CypA

Summary for 8TBG

• Entry DOI: 10.2210/pdb8tbg/pdb
• Descriptor: GTPase HRas, Peptidyl-prolyl cis-trans isomerase A, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (7 entities in total)
• Functional Keywords: inhibitor, complex, small gtpase, cancer, tricomplex, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 77026.93

Authors

Chen, A.,Tomlinson, A.C.A.,Knox, J.E.,Yano, J.K. (deposition date: 2023-06-28, release date: 2024-02-07, Last modification date: 2024-06-05)

Primary citation

Holderfield, M.,Lee, B.J.,Jiang, J.,Tomlinson, A.,Seamon, K.J.,Mira, A.,Patrucco, E.,Goodhart, G.,Dilly, J.,Gindin, Y.,Dinglasan, N.,Wang, Y.,Lai, L.P.,Cai, S.,Jiang, L.,Nasholm, N.,Shifrin, N.,Blaj, C.,Shah, H.,Evans, J.W.,Montazer, N.,Lai, O.,Shi, J.,Ahler, E.,Quintana, E.,Chang, S.,Salvador, A.,Marquez, A.,Cregg, J.,Liu, Y.,Milin, A.,Chen, A.,Ziv, T.B.,Parsons, D.,Knox, J.E.,Klomp, J.E.,Roth, J.,Rees, M.,Ronan, M.,Cuevas-Navarro, A.,Hu, F.,Lito, P.,Santamaria, D.,Aguirre, A.J.,Waters, A.M.,Der, C.J.,Ambrogio, C.,Wang, Z.,Gill, A.L.,Koltun, E.S.,Smith, J.A.M.,Wildes, D.,Singh, M.
Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy.
Nature, 629:919-926, 2024

PubMed Abstract: RAS oncogenes (collectively NRAS, HRAS and especially KRAS) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 and 61. Small molecule inhibitors of the KRAS(G12C) oncoprotein have demonstrated clinical efficacy in patients with multiple cancer types and have led to regulatory approvals for the treatment of non-small cell lung cancer. Nevertheless, KRAS mutations account for only around 15% of KRAS-mutated cancers, and there are no approved KRAS inhibitors for the majority of patients with tumours containing other common KRAS mutations. Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Preclinically, RMC-7977 demonstrated potent activity against RAS-addicted tumours carrying various RAS genotypes, particularly against cancer models with KRAS codon 12 mutations (KRAS). Treatment with RMC-7977 led to tumour regression and was well tolerated in diverse RAS-addicted preclinical cancer models. Additionally, RMC-7977 inhibited the growth of KRAS cancer models that are resistant to KRAS(G12C) inhibitors owing to restoration of RAS pathway signalling. Thus, RAS(ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS(ON) multi-selective inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS-mutant solid tumours (ClinicalTrials.gov identifier: NCT05379985).

PubMed: 38589574
DOI: 10.1038/s41586-024-07205-6

Experimental method

X-RAY DIFFRACTION (1.2 Å)