Necroptosis is a process of a highly regulated necrotic cell death, which has been implicated in the pathogenesis of a variety of poorly treatable diseases including myocardial infarction, brain ischemia, and a variety of inflammatory conditions. Necroptosis is controlled by a "necrosome" complex of two homologous kinases, Receptor Interacting Protein Kinases 1 and 3 (RIP1 and RIP3). Small molecule inhibitors of these kinases attracted significant interest therapeutically. Our previously published cell based screen identified three structurally dissimilar small molecule inhibitors of RIP1 kinase, termed necrostatins. Further work demonstrated that necrostatins displayed potent inhibition of necroptosis through targeting RIPK1 kinase in vitro and in vivo. Furthermore, these molecules displayed unexpected mono-selectivity towards RIPK1 kinase. We present the analysis of the molecular basis for this unusual selectivity using a combination of site directed mutagenesis, structural biology and molecular modeling approaches. Furthermore, using the conclusions from this analysis, we describe development of the more potent and equally highly selective allosteric inhibitors of RIPK1 kinase.<br/>

Development of the selective, allosteric RIPK1 kinase inhibitors

253rd National Meeting (2017)

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