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RIPK2 mediates pro-inflammatory signaling from the bacterial sensors NOD1 and NOD2, and is an emerging therapeutic target in autoimmune and inflammatory diseases. We observed that cellular RIPK2 can be potently inhibited by type II inhibitors that displace the kinase activation segment, whereas ATP-competitive type I inhibition was only poorly effective. The most potent RIPK2 inhibitors were the US Food and Drug Administration-approved drugs ponatinib and regorafenib. Their mechanism of action was independent of NOD2 interaction and involved loss of downstream kinase activation as evidenced by lack of RIPK2 autophosphorylation. Notably, these molecules also blocked RIPK2 ubiquitination and, consequently, inflammatory nuclear factor κB signaling. In monocytes, the inhibitors selectively blocked NOD-dependent tumor necrosis factor production without affecting lipopolysaccharide-dependent pathways. We also determined the first crystal structure of RIPK2 bound to ponatinib, and identified an allosteric site for inhibitor development. These results highlight the potential for type II inhibitors to treat indications of RIPK2 activation as well as inflammation-associated cancers.

Original publication

DOI

10.1016/j.chembiol.2015.07.017

Type

Journal article

Journal

Chem Biol

Publication Date

17/09/2015

Volume

22

Pages

1174 - 1184

Keywords

Amino Acid Sequence, Animals, Cells, Cultured, Humans, Imidazoles, Inflammation, Models, Molecular, Molecular Sequence Data, Nod1 Signaling Adaptor Protein, Nod2 Signaling Adaptor Protein, Protein Binding, Protein Kinase Inhibitors, Pyridazines, Receptor-Interacting Protein Serine-Threonine Kinase 2, Sf9 Cells, Signal Transduction, Ubiquitination