8TBM

Tricomplex of RMC-7977, KRAS G12V, and CypA

8TBM の概要

• エントリーDOI: 10.2210/pdb8tbm/pdb
• 分子名称: GTPase KRas, Peptidyl-prolyl cis-trans isomerase A, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (7 entities in total)
• 機能のキーワード: inhibitor, complex, small gtpase, cancer, tricomplex, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 77964.28

構造登録者

Tomlinson, A.C.A.,Chen, A.,Knox, J.E.,Yano, J.K. (登録日: 2023-06-28, 公開日: 2024-02-07, 最終更新日: 2024-06-05)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.57 Å)