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Effect of Narrow Spectrum Versus Selective Kinase Inhibitors on the Intestinal Proinflammatory Immune Response in
Paolo Biancheri1, Martyn R Foster, Matthew C T Fyfe
1*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.
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.
Insights
Multikinase inhibition with TOP1210 shows potent anti-inflammatory effects against key kinases and cytokines. This broad-spectrum approach offers advantages over selective inhibitors for inflammatory bowel disease treatment.
Area of Science:
- Immunology
- Pharmacology
- Molecular Biology
Background:
- Kinases are central to inflammation, making kinase inhibitors promising for inflammatory disorders.
- Selective kinase inhibitors have shown limited success in conditions like rheumatoid arthritis and inflammatory bowel disease.
- Multikinase inhibition is being explored to enhance therapeutic efficacy.
Purpose of the Study:
- To compare the anti-inflammatory activity of a narrow-spectrum kinase inhibitor, TOP1210, with selective kinase inhibitors.
- To evaluate the efficacy of TOP1210 in various kinase assays, cellular models, and patient-derived inflamed biopsies.
Main Methods:
- Assessed kinase activity (P38α, Src, Syk) using Z-lyte assays.
- Measured proinflammatory cytokine release from immune cells, cell lines, and ulcerative colitis (UC) biopsies.
- Compared TOP1210 with selective inhibitors (BIRB-796, dasatinib, BAY-61-3606).
Main Results:
- TOP1210 potently inhibited P38α, Src, and Syk kinase activities.
- TOP1210 demonstrated strong inhibition of proinflammatory cytokine release in all tested models.
- Selective inhibitors showed weaker cellular activity compared to TOP1210, but combinations improved efficacy.
Conclusions:
- Targeted multikinase inhibition with TOP1210 provides broad efficacy across innate and adaptive immune responses.
- TOP1210 offers significant advantages over selective kinase inhibitors for inflammatory bowel disease.
- TOP1210 holds potential for improved therapeutic benefit in inflammatory bowel disease.
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