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Effect of narrow spectrum versus selective kinase inhibitors on the intestinal proinflammatory immune tesponse in ulcerative colitis
- Source :
- Inflammatory Bowel Diseases
- Publication Year :
- 2016
-
Abstract
- Article first published online 22 April 2016.<br />Background: Kinases are key mediators of inflammation, highlighting the potential of kinase inhibitors as treatments for inflammatory disorders. Selective kinase inhibitors, however, have proved disappointing, particularly in the treatment of rheumatoid arthritis and inflammatory bowel disease. Consequently, to improve efficacy, attention has turned to multikinase inhibition. Methods: The activity of a narrow spectrum kinase inhibitor, TOP1210, has been compared with selective kinase inhibitors (BIRB-796, dasatinib and BAY-61-3606) in a range of kinase assays, inflammatory cell assays, and in inflamed biopsies from patients with ulcerative colitis (UC). Effects on recombinant P38α, Src, and Syk kinase activities were assessed using Z-lyte assays (Invitrogen, Paisley, United Kingdom). Anti-inflammatory effects were assessed by measurement of proinflammatory cytokine release from peripheral blood mononuclear cells, primary macrophages, HT29 cells, inflamed colonic UC biopsies, and myofibroblasts isolated from inflamed colonic UC mucosa. Results: TOP1210 potently inhibits P38α, Src, and Syk kinase activities. Similarly, TOP1210 demonstrates potent inhibitory activity against proinflammatory cytokine release in each of the cellular assays and the inflamed colonic UC biopsies and myofibroblasts isolated from inflamed colonic UC mucosa. Generally, the selective kinase inhibitors showed limited and weaker activity in the cellular assays compared with the broad inhibitory profile of TOP1210. However, combination of the selective inhibitors led to improved efficacy and potency in both cellular and UC biopsy assays. Conclusions: Targeted, multikinase inhibition with TOP1210 leads to a broad efficacy profile in both the innate and adaptive immune responses, with significant advantages over existing selective kinase approaches, and potentially offers a much improved therapeutic benefit in inflammatory bowel disease.
- Subjects :
- 0301 basic medicine
MAPK/ERK pathway
Niacinamide
medicine.drug_class
Biopsy
Primary Cell Culture
Dasatinib
Original Basic Science Articles
Syk
Pharmacology
Naphthalenes
Fostamatinib
Mitogen-Activated Protein Kinase 14
03 medical and health sciences
0302 clinical medicine
medicine
Immunology and Allergy
Humans
Syk Kinase
Protein kinase A
Myofibroblasts
narrow spectrum kinase inhibitor
Protein Kinase Inhibitors
ulcerative colitis
business.industry
Kinase
Macrophages
Interleukin-8
TOP1210
Gastroenterology
Protein kinase inhibitor
030104 developmental biology
Pyrimidines
src-Family Kinases
Benzamides
Leukocytes, Mononuclear
Cytokines
Pyrazoles
030211 gastroenterology & hepatology
Colitis, Ulcerative
Signal transduction
Janus kinase
business
HT29 Cells
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Inflammatory Bowel Diseases
- Accession number :
- edsair.doi.dedup.....570ef2437fd45d47ca129b48b4a4cdc0