Journal
CHEMISTRY & BIOLOGY
Volume 22, Issue 9, Pages 1174-1184Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2015.07.017
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Funding
- Crohn's & Colitis Foundation of America (CCFA)
- Leona M. and Harry B. Helmsley Charitable Trust
- Deutsche Forschungsgemeinschaft [SCHW1730/1-1]
- National Institute of General Medical Sciences [R01GM080356, R01GM084205]
- Wellcome Trust Fellowship [102894/Z/13/Z]
- Ludwig Cancer Research
- Sapere Aude: Danish Council for independent Research-Starting Grant
- EMBO Young Investigator Programme
- AbbVie, Bayer [1097737]
- Boehringer Ingelheim
- Genome Canada through Ontario Genomics Institute [OGI-055]
- GlaxoSmithKline
- Janssen
- Lilly Canada
- Novartis Research Foundation
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Takeda
- Wellcome Trust [092809/Z/10/Z]
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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 kappa B 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.
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