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Inflammatory Signaling by NOD-RIPK2 Is Inhibited by Clinically Relevant Type II Kinase Inhibitors

DOI: 10.1016/j.chembiol.2015.07.017 DOI Help

Authors: Peter Canning (University of Oxford) , Qui Ruan (Tufts University School of Medicine) , Tobias Schwerd (University of Oxford) , Matous Hrdinka (University of Oxford) , Jenny l. Maki (Tufts University School of Medicine) , Danish Saleh (Tufts University School of Medicine) , Chalada Suebsuwong (University of Houston) , Soumya Ray (Brigham & Women's Hospital and Harvard Medical School, Cambridge) , Paul Brennan (University of Oxford) , Gregory Cuny (University of Houston) , Holm Uhlig (University of Oxford) , Mads Gyrd-hansen (University of Oxford) , Alexei Degterev (Tufts University School of Medicine) , Alex Bullock (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemistry & Biology , VOL 22 (9) , PAGES 1174 - 1184

State: Published (Approved)
Published: September 2015
Diamond Proposal Number(s): 8421

Open Access Open Access

Abstract: 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.

Journal Keywords: Structural Genomics Consortium

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I04-Macromolecular Crystallography