title: In vivo inhibition of RIPK2 kinase alleviates inflammatory disease.
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.
authors.affiliation: From the Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106-4973.
authors.forename: Justine T
authors.initials: JT
authors.lastname: Tigno-Aranjuez
authors.affiliation: Oncodesign S.A., 20, Rue Jean Mazen, B.P. 27 627, 21 076 Dijon Cedex, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Benderitter
authors.affiliation: Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Frederik
authors.initials: F
authors.lastname: Rombouts
authors.affiliation: Asclepia Outsourcing Solutions, Damvalleistraat 49, B-9070 Destelbergen, Belgium.
authors.forename: Frederik
authors.initials: F
authors.lastname: Deroose
authors.affiliation: RNA Center, Case Western Reserve University, Cleveland, Ohio 44106-4973, and.
authors.forename: XiaoDong
authors.initials: X
authors.lastname: Bai
authors.affiliation: From the Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106-4973.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Mattioli
authors.affiliation: 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.
authors.forename: Fabio
authors.initials: F
authors.lastname: Cominelli
authors.affiliation: From the Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106-4973.
authors.forename: Theresa T
authors.initials: TT
authors.lastname: Pizarro
authors.affiliation: Oncodesign S.A., 20, Rue Jean Mazen, B.P. 27 627, 21 076 Dijon Cedex, France.
authors.forename: Jan
authors.initials: J
authors.lastname: Hoflack
authors.affiliation: From the Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106-4973, dwa4@case.edu.
authors.forename: Derek W
authors.initials: DW
authors.lastname: Abbott
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine; D000818:Animals; D003424:Crohn Disease / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling; D005819:Genetic Markers; D057809:HEK293 Cells; D006801:Humans; D007079:Ileitis / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008810:Mice, Inbred C57BL; D010538:Peritonitis / Q000139:chemically induced / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013379:Substrate Specificity / Q000187:drug effects; D059467:Transcriptome / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D005819:Genetic Markers; D047428:Protein Kinase Inhibitors; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2
keywords: Dual Specificity Kinase; Enzyme Inhibitor; Immunology; Innate Immunity; Nod-like Receptor (NLR); Signal Transduction