Article abstract

Nature Chemical Biology 4, 313 - 321 (2008)
Published online: 13 April 2008 | doi:10.1038/nchembio.83

Identification of RIP1 kinase as a specific cellular target of necrostatins

Alexei Degterev1,2, Junichi Hitomi2, Megan Germscheid1, Irene L Ch'en3, Olga Korkina1, Xin Teng4, Derek Abbott5,9, Gregory D Cuny4, Chengye Yuan6, Gerhard Wagner7, Stephen M Hedrick3, Scott A Gerber8, Alexey Lugovskoy7,9 & Junying Yuan2

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.

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  1. Tufts University, School of Medicine, Department of Biochemistry, 136 Harrison Avenue, Boston, Massachusetts 02111, USA.
  2. Harvard Medical School, Department of Cell Biology, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.
  3. Division of Biological Sciences and the Department of Cellular and Molecular Medicine, 5121 Natural Sciences Building, University of California, San Diego, California 92093-0377, USA.
  4. Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham & Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, USA.
  5. Department of Systems Biology, Harvard Medical School, and Division of Signal Transduction, Beth Israel Deaconess Medical Center, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
  6. Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China.
  7. Harvard Medical School, Department of Biological Chemistry and Molecular Pharmacology, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.
  8. Department of Genetics, Norris Cotton Cancer Center and Dartmouth Medical School, 7400 Remsen, Hanover, New Hampshire 03755, USA.
  9. 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.).

Correspondence to: Alexei Degterev1,2 e-mail: alexei.degterev@tufts.edu

Correspondence to: Junying Yuan2 e-mail: jyuan@hms.harvard.edu



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