7RSJ

Structure of the VPS34 kinase domain with compound 14

7RSJ の概要

• エントリーDOI: 10.2210/pdb7rsj/pdb
• 分子名称: Phosphatidylinositol 3-kinase catalytic subunit type 3, SODIUM ION, N-{4-[(7R,8R)-4-oxo-7-(propan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]pyridin-2-yl}cyclopropanecarboxamide, ... (6 entities in total)
• 機能のキーワード: vps34 inhibitor, endosomal trafficking, authophagy, oncoprotein, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 70730.55

構造登録者

Hu, D.X.,Patel, S.,Chen, H.,Wang, S.,Staben, S.,Dimitrova, Y.N.,Wallweber, H.A.,Lee, J.Y.,Chan, G.K.Y.,Sneeringer, C.J.,Prangley, M.S.,Moffat, J.G.,Wu, C.,Schutt, L.K.,Salphati, L.,Pang, J.,McNamara, E.,Huang, H.,Chen, Y.,Wang, Y.,Zhao, W.,Lim, J.,Murthy, A.,Siu, M. (登録日: 2021-08-11, 公開日: 2021-11-24, 最終更新日: 2024-04-03)

主引用文献

Hu, D.X.,Patel, S.,Chen, H.,Wang, S.,Staben, S.T.,Dimitrova, Y.N.,Wallweber, H.A.,Lee, J.Y.,Chan, G.K.Y.,Sneeringer, C.J.,Prangley, M.S.,Moffat, J.G.,Wu, K.C.,Schutt, L.K.,Salphati, L.,Pang, J.,McNamara, E.,Huang, H.,Chen, Y.,Wang, Y.,Zhao, W.,Lim, J.,Murthy, A.,Siu, M.
Structure-Based Design of Potent, Selective, and Orally Bioavailable VPS34 Kinase Inhibitors.
J.Med.Chem., 65:11500-11512, 2022

PubMed Abstract: VPS34 is a class III phosphoinositide 3-kinase involved in endosomal trafficking and autophagosome formation. Inhibitors of VPS34 were believed to have value as anticancer agents, but genetic and pharmacological data suggest that sustained inhibition of VPS34 kinase activity may not be well tolerated. Here we disclose the identification of a novel series of dihydropyrazolopyrazinone compounds represented by compound as potent, selective, and orally bioavailable VPS34 inhibitors through a structure-based design strategy. A water-interacting hydrogen bond acceptor within an appropriate distance to a hinge-binding element was found to afford significant VPS34 potency across chemical scaffolds. The selectivity of compound over PIK family kinases arises from interactions between the hinge-binding element and the pseudo-gatekeeper residue Met682. As recent in vivo pharmacology data suggests that sustained inhibition of VPS34 kinase activity may not be tolerated, structure-activity relationships leading to VPS34 inhibition may be helpful for avoiding this target in other ATP-competitive kinase programs.

PubMed: 34779204
DOI: 10.1021/acs.jmedchem.1c01180

実験手法

X-RAY DIFFRACTION (1.881 Å)