Receptor interacting protein kinase 3 (RIPK3) is a critical kinase in the necroptotic cell death signaling pathway.  Necroptosis has been associated with a variety of diseases, and as a result, there is a high interest in selectively targeting the kinases and pseudokinase which participate in this cell death pathway.  As a means to identify non-Type I inhibitors for RIPK3, mechanistic studies were incorporated into the hit triage phase of high throughput screening (HTS).  Relying on high throughput time dependency (TD) and mode of inhibition (MOI) studies, a putative Type II inhibitor was identified.  Protein crystallography confirmed that the inhibitor was binding in a DFG-out conformation in RIPK3.  This represents the first non-Type I RIPK3 inhibitor reported. <br/>

Identification of receptor interacting protein kinase 3 (RIPK3) type II inhibitors using high-throughput mechanistic studies in hit triage

256th National Meeting (2018)

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