6R5F

Crystal structure of RIP1 kinase in complex with DHP77

Summary for 6R5F

• Entry DOI: 10.2210/pdb6r5f/pdb
• Descriptor: 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)
• Functional Keywords: inhibitor, complex, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 139897.12

Authors

Thorpe, J.H.,Campobasso, N.,Harris, P.A. (deposition date: 2019-03-25, release date: 2019-05-01, Last modification date: 2024-01-24)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3.25 Å)