6R5F

Crystal structure of RIP1 kinase in complex with DHP77

6R5F の概要

• エントリーDOI: 10.2210/pdb6r5f/pdb
• 分子名称: Receptor-interacting serine/threonine-protein kinase 1, [(5~{S})-5-[3,5-bis(fluoranyl)phenyl]pyrazolidin-1-yl]-[1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl]methanone (2 entities in total)
• 機能のキーワード: inhibitor, complex, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 139897.12

構造登録者

Thorpe, J.H.,Campobasso, N.,Harris, P.A. (登録日: 2019-03-25, 公開日: 2019-05-01, 最終更新日: 2024-01-24)

主引用文献

Harris, P.A.,Faucher, N.,George, N.,Eidam, P.M.,King, B.W.,White, G.V.,Anderson, N.A.,Bandyopadhyay, D.,Beal, A.M.,Beneton, V.,Berger, S.B.,Campobasso, N.,Campos, S.,Capriotti, C.A.,Cox, J.A.,Daugan, A.,Donche, F.,Fouchet, M.H.,Finger, J.N.,Geddes, B.,Gough, P.J.,Grondin, P.,Hoffman, B.L.,Hoffman, S.J.,Hutchinson, S.E.,Jeong, J.U.,Jigorel, E.,Lamoureux, P.,Leister, L.K.,Lich, J.D.,Mahajan, M.K.,Meslamani, J.,Mosley, J.E.,Nagilla, R.,Nassau, P.M.,Ng, S.L.,Ouellette, M.T.,Pasikanti, K.K.,Potvain, F.,Reilly, M.A.,Rivera, E.J.,Sautet, S.,Schaeffer, M.C.,Sehon, C.A.,Sun, H.,Thorpe, J.H.,Totoritis, R.D.,Ward, P.,Wellaway, N.,Wisnoski, D.D.,Woolven, J.M.,Bertin, J.,Marquis, R.W.
Discovery and Lead-Optimization of 4,5-Dihydropyrazoles as Mono-Kinase Selective, Orally Bioavailable and Efficacious Inhibitors of Receptor Interacting Protein 1 (RIP1) Kinase.
J.Med.Chem., 62:5096-5110, 2019

PubMed Abstract: RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently, RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis and neurological diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. In this paper, we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead-optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species. Additionally, we identified a potent murine RIP1 kinase inhibitor 76 as a valuable in vivo tool molecule suitable for evaluating the role of RIP1 kinase in chronic models of disease. DHP 76 showed efficacy in mouse models of both multiple sclerosis and human retinitis pigmentosa.

PubMed: 31013427
DOI: 10.1021/acs.jmedchem.9b00318

実験手法

X-RAY DIFFRACTION (3.25 Å)