5KCV

Crystal structure of allosteric inhibitor, ARQ 092, in complex with autoinhibited form of AKT1

5KCV の概要

• エントリーDOI: 10.2210/pdb5kcv/pdb
• 分子名称: RAC-alpha serine/threonine-protein kinase, 3-[3-[4-(1-azanylcyclobutyl)phenyl]-5-phenyl-imidazo[4,5-b]pyridin-2-yl]pyridin-2-amine (3 entities in total)
• 機能のキーワード: akt, allosteric inhibitor, kinase inhibitor, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: P31749
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 53990.53

構造登録者

Eathiraj, S. (登録日: 2016-06-07, 公開日: 2016-06-29, 最終更新日: 2024-11-06)

主引用文献

Lapierre, J.M.,Eathiraj, S.,Vensel, D.,Liu, Y.,Bull, C.O.,Cornell-Kennon, S.,Iimura, S.,Kelleher, E.W.,Kizer, D.E.,Koerner, S.,Makhija, S.,Matsuda, A.,Moussa, M.,Namdev, N.,Savage, R.E.,Szwaya, J.,Volckova, E.,Westlund, N.,Wu, H.,Schwartz, B.
Discovery of 3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor.
J.Med.Chem., 59:6455-6469, 2016

PubMed Abstract: The work in this paper describes the optimization of the 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine chemical series as potent, selective allosteric inhibitors of AKT kinases, leading to the discovery of ARQ 092 (21a). The cocrystal structure of compound 21a bound to full-length AKT1 confirmed the allosteric mode of inhibition of this chemical class and the role of the cyclobutylamine moiety. Compound 21a demonstrated high enzymatic potency against AKT1, AKT2, and AKT3, as well as potent cellular inhibition of AKT activation and the phosphorylation of the downstream target PRAS40. Compound 21a also served as a potent inhibitor of the AKT1-E17K mutant protein and inhibited tumor growth in a human xenograft mouse model of endometrial adenocarcinoma.

PubMed: 27305487
DOI: 10.1021/acs.jmedchem.6b00619

実験手法

X-RAY DIFFRACTION (2.7 Å)