Effect of Narrow Spectrum Versus Selective Kinase Inhibitors on the Intestinal Proinflammatory Immune Response in Ulcerative Colitis.
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.



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.



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.



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.
*Centre for Immunobiology, Barts and the London School of Medicine and Dentistry, London, United Kingdom; †Topivert Pharma Ltd., London, United Kingdom; and ‡Academic Department of Medical and Surgical Gastroenterology, Homerton University Hospital, London, United Kingdom.
Paolo
P
Biancheri
Martyn R
MR
Foster
Matthew C T
MC
Fyfe
Thomas T
TT
MacDonald
Sameer
S
Sirohi
Yemisi
Y
Solanke
Eleanor
E
Wood
Adele
A
Rowley
Steve
S
Webber
Claire A
CA
Walshe
D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D001706:Biopsy; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism*; D000069439:Dasatinib / Q000494:pharmacology / Q000627:therapeutic use*; D019073:HT29 Cells; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000378:metabolism; D058628:Myofibroblasts / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology / Q000627:therapeutic use*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D000072377:Syk Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010671:Phenylurea Compounds
D001549:Benzamides; D016207:Cytokines; D000069439:Dasatinib; D016209:Interleukin-8; D048308:Mitogen-Activated Protein Kinase 14; D009281:Naphthalenes; D009536:Niacinamide; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D000072377:Syk Kinase; D019061:src-Family Kinases; C477642:2-(7-(3,4-dimethoxyphenyl)imidazo(1,2-c)pyrimidin-5-ylamino)nicotinamide; C000626264:TOP1210; C452139:doramapimod; D010671:Phenylurea Compounds