Receptor interacting protein kinase 2 (RIPK2) is a caspase recruitment domain (CARD) containing kinase that has been implicated in nucleotide binding and oligomerization domain 1 and 2 (NOD1 and NOD2) signaling. NOD1/2-RIPK2 interactions result in activation of nuclear factor κB (NF-κB) and mitogen-activated protein (MAP) kinase pathways to promote transcription of pro-inflammatory cytokines that associate with pathogenesis of inflammatory diseases such as inflammatory bowel disease (IBD), Crohn’s disease, ulcerative colitis and multiple sclerosis.<br/><br/>Published RIPK2 crystal structures in complex with different inhibitors reveal that RIPK2 protein can adopt both active (DFG-in/Glu-in) and inactive (DFG-out/Glu-in and DFG-in/αC-helix-out) kinase conformations. One strategy for improving kinase selectivity is targeting structurally distinct inactive kinase conformations. This presentation will report a hybridization strategy to achieve potent and selective allosteric, αC-helix-displacing inhibitors of RIPK2.

Hybridization approach to selective RIPK2 inhibitors by targeting inactive kinase conformations

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.