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 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.




Copyright 2008 Nature Chemical Biology. This is a post-print version of a published paper that is available at: Recommended citation: Degterev, Alexei, Junichi Hitomi, Megan Germscheid, Irene L. Ch'en, Olga Korkina, Xin Teng, Derek Abbott et al. "Identification of RIP1 kinase as a specific cellular target of necrostatins." Nature chemical biology 4, no. 5 (2008): 313. doi: 10.1038/nchembio.83. This item has been deposited in accordance with publisher copyright and licensing terms and with the author's permission.