6r5f
From Proteopedia
Crystal structure of RIP1 kinase in complex with DHP77
Structural highlights
FunctionRIPK1_HUMAN Serine-threonine kinase which transduces inflammatory and cell-death signals (programmed necrosis) following death receptors ligation, activation of pathogen recognition receptors (PRRs), and DNA damage. Upon activation of TNFR1 by the TNF-alpha family cytokines, TRADD and TRAF2 are recruited to the receptor. Ubiquitination by TRAF2 via 'Lys-63'-link chains acts as a critical enhancer of communication with downstream signal transducers in the mitogen-activated protein kinase pathway and the NF-kappa-B pathway, which in turn mediate downstream events including the activation of genes encoding inflammatory molecules. Polyubiquitinated protein binds to IKBKG/NEMO, the regulatory subunit of the IKK complex, a critical event for NF-kappa-B activation. Interaction with other cellular RHIM-containing adapters initiates gene activation and cell death. RIPK1 and RIPK3 association, in particular, forms a necrosis-inducing complex.[1] [2] [3] Publication Abstract from PubMedRIP1 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 neuro-logical diseases such as amyotrophic lateral sclerosis (ALS) 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. Discovery and Lead-optimization of 4,5-Dihydropyrazoles as Mono-Kinase Selective, Orally Bioavailable and Efficacious Inhibitors of Receptor Interacting Protein 1 (RIP1) Kinase.,Harris PA, Faucher N, George N, Eidam PM, King BW, White G, Anderson NA, Bandyopadhyay D, Beal AM, Beneton V, Berger SB, Campobasso N, Campos S, Capriotti CA, Cox JA, Daugan A, Donche F, Fouchet MH, Finger JN, Geddes B, Gough PJ, Grondin P, Hoffman B, Hoffman SJ, Hutchinson S, Jeong JU, Jigorel E, Lamoureux P, Leister LK, Lich JD, Mahajan MK, Meslamani J, Mosley JE, Nagilla R, Nassau P, Ng SL, Ouellette MT, Pasikanti K, Potvain F, Reilly MA, Rivera EJ, Sautet S, Schaeffer MC, Sehon CA, Sun HH, Thorpe JH, Totoritis RD, Ward P, Wellaway N, Wisnoski DD, Woolven JM, Bertin J, Marquis RW J Med Chem. 2019 Apr 23. doi: 10.1021/acs.jmedchem.9b00318. PMID:31013427[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|