2. Academic Validation
  3. In vivo inhibition of RIPK2 kinase alleviates inflammatory disease

In vivo inhibition of RIPK2 kinase alleviates inflammatory disease

  • J Biol Chem. 2014 Oct 24;289(43):29651-64. doi: 10.1074/jbc.M114.591388.
Justine T Tigno-Aranjuez 1,  Pascal Benderitter 2,  Frederik Rombouts 3,  Frederik Deroose 4,  XiaoDong Bai 5,  Benedetta Mattioli 1,  Fabio Cominelli 6,  Theresa T Pizarro 1,  Jan Hoflack 2,  Derek W Abbott 7
Affiliations

Affiliations

  • 1 From the Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106-4973.
  • 2 Oncodesign S.A., 20, Rue Jean Mazen, B.P. 27 627, 21 076 Dijon Cedex, France.
  • 3 Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • 4 Asclepia Outsourcing Solutions, Damvalleistraat 49, B-9070 Destelbergen, Belgium.
  • 5 RNA Center, Case Western Reserve University, Cleveland, Ohio 44106-4973, and.
  • 6 From the Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106-4973, Division of Gastroenterology, Department of Medicine, University Hospitals of Cleveland, Cleveland, Ohio 44106-4973.
  • 7 From the Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106-4973, dwa4@case.edu.
PMID: 25213858 DOI: 10.1074/jbc.M114.591388
Abstract

The RIPK2 kinase transduces signaling downstream of the intracellular peptidoglycan sensors NOD1 and NOD2 to promote a productive inflammatory response. However, excessive NOD2 signaling has been associated with numerous diseases, including inflammatory bowel disease (IBD), sarcoidosis and inflammatory arthritis, making pharmacologic inhibition of RIPK2 an appealing strategy. In this work, we report the generation, identification, and evaluation of novel RIPK2 specific inhibitors. These compounds potently inhibit the RIPK2 tyrosine kinase activity in in vitro biochemical assays and cellular assays, as well as effectively reduce RIPK2-mediated effects in an in vivo peritonitis model. In conjunction with the development of these inhibitors, we have also defined a panel of genes whose expression is regulated by RIPK2 kinase activity. Such RIPK2 activation markers may serve as a useful tool for predicting settings likely to benefit from RIPK2 inhibition. Using these markers and the FDA-approved RIPK2 Inhibitor Gefitinib, we show that pharmacologic RIPK2 inhibition drastically improves disease in a spontaneous model of Crohn Disease-like ileitis. Furthermore, using novel RIPK2-specific inhibitors, we show that cellular recruitment is inhibited in an in vivo peritonitis model. Altogether, the data presented in this work provides a strong rationale for further development and optimization of RIPK2-targeted pharmaceuticals and diagnostics.

Keywords

Dual Specificity Kinase; Enzyme Inhibitor; Immunology; Innate Immunity; Nod-like Receptor (NLR); Signal Transduction.

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