1. The potent and selective RIPK2 inhibitor BI 706039 improves intestinal inflammation in the TRUC mouse model of inflammatory bowel disease
- Author
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Emma K. Haley, Diane Mierz, Mark Panzenbeck, Steve Fogal, M. Lamine Mbow, Mederbek Matmusaev, Susan Lukas, Svenja Mayer-Wrangowski, Miller Craig Andrew, Jie Zheng, F. James King, Clemens Braun, Fergus R. Byrne, Joerg Ermann, Donna Terenzio, Li Li, Felix Jost, Jay S. Fine, Lori Patnaude, Naitee Ting, Alex P. Klimowicz, Jane Chime, Tom Simpson, Peng Hsiao, and David Csordas
- Subjects
Oral dose ,medicine.medical_specialty ,Physiology ,Colon ,Biological Availability ,Inflammation ,Inflammatory bowel disease ,Gastroenterology ,Models, Biological ,Monocytes ,RIPK2 ,Feces ,Crohn Disease ,Intestinal inflammation ,Receptor-Interacting Protein Serine-Threonine Kinase 2 ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Humans ,Microbiome ,Protein Kinase Inhibitors ,Cells, Cultured ,Mice, Knockout ,Mice, Inbred BALB C ,Hepatology ,business.industry ,Kinase ,medicine.disease ,Lipocalins ,Apex (geometry) ,DNA-Binding Proteins ,Disease Models, Animal ,Cytokines ,Colitis, Ulcerative ,medicine.symptom ,Inflammation Mediators ,business ,T-Box Domain Proteins - Abstract
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
- Published
- 2021