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P032 The pharmacological profile of TOP1288, a narrow spectrum kinase inhibitor in clinical development as an anti-inflammatory treatment for ulcerative colitis

Foster M.*1, Biancheri P.2, Fyfe M.1, MacDonald T.3, Rowley A.1, Sirohi S.1, Solanke Y.1, Webber S.1, Walshe C.1

1Topivert Pharma Ltd, London, United Kingdom 2University of East Anglia, Norwich Medical School, Norwich, United Kingdom 3Barts and London School of Medicine and Dentistry, Centre of Immunobiology, London, United Kingdom

Background

Intracellular kinase activation plays a key role in inflammation and kinase inhibitors have been proposed as potential therapy for chronic inflammatory disorders such as ulcerative colitis. Selective kinase inhibitors have proved disappointing, particularly in the treatment of rheumatoid arthritis and inflammatory bowel disease (IBD). In a strategy to improve efficacy through multi-kinase inhibition, a series of narrow spectrum kinase inhibitors (NSKIs) have been developed. The activity of TOP1288, an NSKI in clinical development, has been compared to selective kinase inhibitors (BIRB-796, dasatinib and BAY-61–3606) in a range of innate and adaptive inflammatory cell assays. In addition, TOP1288 has been assessed as an inhibitor of inflammatory cytokine release from inflamed biopsies and myofibroblasts from ulcerative colitis (UC) patients.

Methods

Activity of compounds as inhibitors of purified kinases was assessed using ZLYTE™ assays. Anti-inflammatory effects of TOP1288 or selective kinase inhibitors were assessed by measurement of pro-inflammatory cytokine release from peripheral blood mononuclear cells (PBMCs) from healthy donors, primary macrophages and HT29 cells. Similarly, TOP1288 was assessed in inflamed colonic UC biopsies and myofibroblasts isolated from colonic mucosa by measuring spontaneous or TNFα induced cytokine release.

Results

TOP1288 potently inhibited P38α, Src and Syk kinase activity with IC50 values of 116nM, 24nM and 659nM respectively. Similarly, TOP1288 demonstrated efficacious and potent inhibition (IC50 values ranging from 0.6–77 nM) of pro-inflammatory cytokine release from PBMCs from healthy donors, primary macrophages and HT29 epithelial cells. In each cell type, TOP1288 achieved complete inhibition, regardless of the cytokine measured or stimulus used. Generally, the selective kinase inhibitors showed much more limited efficacy and weaker potency in the cellular assays compared to TOP1288. TOP1288 down regulated spontaneous release of IL-1β, IL-6 and IL-8 release from inflamed colonic UC biopsies with an efficacy similar to or greater than prednisolone. Similarly, TOP1288 potently inhibited IL-6 and IL-8 release from TNFα stimulated myofibroblasts isolated from inflamed colonic UC mucosa.

Conclusion

Targeted, multi-kinase inhibition using the NSKI TOP1288 leads to an efficacious and broad inhibitory profile in UC tissues and across a range of cell types including epithelial cells, innate and adaptive immune cells. TOP1288, which is in clinical development, may provide significant advantages over existing selective kinase approaches, and potentially offers a much improved therapeutic benefit in IBD