Identification of RIP1 kinase as a specific cellular target of necrostatins

Necroptosis is a cellular mechanism of necrotic cell death induced by apoptotic stimuli in the form of death domain receptor engagement by their respective ligands under conditions where apoptotic execution is prevented. Although it occurs under regulated conditions, necroptotic cell death is charac...

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Bibliographic Details
Published in:	Nature chemical biology Vol. 4; no. 5; pp. 313 - 321
Main Authors:	Degterev, Alexei, Yuan, Junying, Hitomi, Junichi, Germscheid, Megan, Ch'en, Irene L, Korkina, Olga, Teng, Xin, Abbott, Derek, Cuny, Gregory D, Yuan, Chengye, Wagner, Gerhard, Hedrick, Stephen M, Gerber, Scott A, Lugovskoy, Alexey
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-05-2008 Nature Publishing Group
Subjects:	Animals Apoptosis Biochemical Engineering Biochemistry Bioorganic Chemistry Cell Biology Chemistry Chemistry and Materials Science Chemistry/Food Science Imidazoles - metabolism Mice Mortality Protein Kinase Inhibitors - pharmacology Protein Kinases - metabolism Structure-Activity Relationship
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Summary:	Necroptosis is a cellular mechanism of necrotic cell death induced by apoptotic stimuli in the form of death domain receptor engagement by their respective ligands under conditions where apoptotic execution is prevented. Although it occurs under regulated conditions, necroptotic cell death is characterized by the same morphological features as unregulated necrotic death. Here we report that necrostatin-1, a previously identified small-molecule inhibitor of necroptosis, is a selective allosteric inhibitor of the death domain receptor–associated adaptor kinase RIP1 in vitro . We show that RIP1 is the primary cellular target responsible for the antinecroptosis activity of necrostatin-1. In addition, we show that two other necrostatins, necrostatin-3 and necrostatin-5, also target the RIP1 kinase step in the necroptosis pathway, but through mechanisms distinct from that of necrostatin-1. Overall, our data establish necrostatins as the first-in-class inhibitors of RIP1 kinase, the key upstream kinase involved in the activation of necroptosis.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Present addresses: Department of Pathology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106-7288, USA (D.A.) and Molecular Modeling, Biogen Idec Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, USA (A.L.).
ISSN:	1552-4450 1552-4469
DOI:	10.1038/nchembio.83