The potent and selective RIPK2 inhibitor BI 706039 improves intestinal inflammation in the TRUC mouse model of inflammatory bowel disease.

Autor:	Ermann J; Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Matmusaev M; Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Boston, Massachusetts., Haley EK; Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Boston, Massachusetts., Braun C; Department of Drug Discovery Sciences, Boehringer-Ingelheim Pharmaceuticals Incorporated, Biberach, Germany., Jost F; Department of Drug Discovery Sciences, Boehringer-Ingelheim Pharmaceuticals Incorporated, Biberach, Germany., Mayer-Wrangowski S; Department of Drug Discovery Sciences, Boehringer-Ingelheim Pharmaceuticals Incorporated, Biberach, Germany., Hsiao P; Department of Drug Discovery Sciences, Boehringer-Ingelheim Pharmaceuticals Incorporated, Biberach, Germany., Ting N; Department of Global Computational Biology and Data Sciences, Boehringer-Ingelheim Pharmaceuticals Incorporated, Ridgefield, Connecticut., Li L; Department of Global Computational Biology and Data Sciences, Boehringer-Ingelheim Pharmaceuticals Incorporated, Ridgefield, Connecticut., Terenzio D; Department of Immunology and Respiratory Diseases Research, Boehringer-Ingelheim Pharmaceuticals Incorporated, Ridgefield, Connecticut., Chime J; Department of Immunology and Respiratory Diseases Research, Boehringer-Ingelheim Pharmaceuticals Incorporated, Ridgefield, Connecticut., Lukas S; Department of Immunology and Respiratory Diseases Research, Boehringer-Ingelheim Pharmaceuticals Incorporated, Ridgefield, Connecticut., Patnaude L; Department of Immunology and Respiratory Diseases Research, Boehringer-Ingelheim Pharmaceuticals Incorporated, Ridgefield, Connecticut., Panzenbeck M; Department of Immunology and Respiratory Diseases Research, Boehringer-Ingelheim Pharmaceuticals Incorporated, Ridgefield, Connecticut., Csordas D; Department of Immunology and Respiratory Diseases Research, Boehringer-Ingelheim Pharmaceuticals Incorporated, Ridgefield, Connecticut., Zheng J; Department of Immunology and Respiratory Diseases Research, Boehringer-Ingelheim Pharmaceuticals Incorporated, Ridgefield, Connecticut., Mierz D; Department of Immunology and Respiratory Diseases Research, Boehringer-Ingelheim Pharmaceuticals Incorporated, Ridgefield, Connecticut., Simpson T; Department of Immunology and Respiratory Diseases Research, Boehringer-Ingelheim Pharmaceuticals Incorporated, Ridgefield, Connecticut., King FJ; Department of Immunology and Respiratory Diseases Research, Boehringer-Ingelheim Pharmaceuticals Incorporated, Ridgefield, Connecticut., Klimowicz AP; Department of Immunology and Respiratory Diseases Research, Boehringer-Ingelheim Pharmaceuticals Incorporated, Ridgefield, Connecticut., Mbow ML; Department of Immunology and Respiratory Diseases Research, Boehringer-Ingelheim Pharmaceuticals Incorporated, Ridgefield, Connecticut., Fine JS; Department of Immunology and Respiratory Diseases Research, Boehringer-Ingelheim Pharmaceuticals Incorporated, Ridgefield, Connecticut., Miller CA; Department of Immunology and Respiratory Diseases Research, Boehringer-Ingelheim Pharmaceuticals Incorporated, Ridgefield, Connecticut., Fogal SE; Department of Immunology and Respiratory Diseases Research, Boehringer-Ingelheim Pharmaceuticals Incorporated, Ridgefield, Connecticut., Byrne FR; Department of Immunology and Respiratory Diseases Research, Boehringer-Ingelheim Pharmaceuticals Incorporated, Ridgefield, Connecticut.
Jazyk:	angličtina
Zdroj:	American journal of physiology. Gastrointestinal and liver physiology [Am J Physiol Gastrointest Liver Physiol] 2021 Nov 01; Vol. 321 (5), pp. G500-G512. Date of Electronic Publication: 2021 Sep 08.
DOI:	10.1152/ajpgi.00163.2021
Abstrakt:	Mouse and human data implicate the NOD1 and NOD2 sensors of the intestinal microbiome and the associated signal transduction via the receptor interacting protein kinase 2 (RIPK2) as a potential key signaling node for the development of inflammatory bowel disease (IBD) and an attractive target for pharmacological intervention. The TRUC mouse model of IBD was strongly indicated for evaluating RIPK2 antagonism for its effect on intestinal inflammation based on previous knockout studies with NOD1, NOD2, and RIPK2. We identified and profiled the BI 706039 molecule as a potent and specific functional inhibitor of both human and mouse RIPK2 and with favorable pharmacokinetic properties. We dosed BI 706039 in the spontaneous TRUC mouse model from age 28 to 56 days. Oral, daily administration of BI 706039 caused dose-responsive and significant improvement in colonic histopathological inflammation, colon weight, and terminal levels of protein-normalized fecal lipocalin (all P values <0.001). These observations correlated with dose responsively increasing systemic levels of the BI 706039 compound, splenic molecular target engagement of RIPK2, and modulation of inflammatory genes in the colon. This demonstrates that a relatively low oral dose of a potent and selective RIPK2 inhibitor can modulate signaling in the intestinal immune system and significantly improve disease associated intestinal inflammation. NEW & NOTEWORTHY The RIPK2 kinase at the apex of microbiome immunosensing is an attractive target for pharmacological intervention. A low oral dose of a RIPK2 inhibitor leads to significantly improved intestinal inflammation in the murine TRUC model of colitis. A selective and potent inhibitor of the RIPK2 kinase may represent a new class of therapeutics that target microbiome-driven signaling for the treatment of IBD.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu