Effects of narrow spectrum vs selective kinase inhibitors on the intestinal pro-inflammatory immune response in IBD

Background & Aims. Intracellular kinase activation plays a pivotal role in intestinal inflammation. We profiled the effects of selective kinase inhibitors and the narrow spectrum kinase inhibitor (NSKI) TOP1106 on innate and adaptive immune mechanisms involved in IBD.

Methods. Inhibition of P38a, Src and Syk kinase activity was assessed by recombinant ZLYTE^TMassays. Peripheral blood mononuclear cells (PBMCs) from healthy donors, HT-29 cells, or inflamed colonic IBD biopsies were cultured with TOP1106 or selective kinase inhibitors with pro-inflammatory cytokine release subsequently assessed by ELISA.

Results. TOP1106 is a potent inhibitor of P38a, Src and Syk kinases. Compared to the selective kinase inhibitors, TOP1106 demonstrated broader activity across a range of innate and adaptive cellular response assays and in IBD organ culture experiments. Generally, the selective kinase inhibitors lacked efficacy and potency compared to TOP1106. Combination of the selective inhibitors led to an improved inhibitory profile in both cellular and IBD biopsy assays, with data indicating that TOP1106 could be achieving its broad anti-inflammatory activity through the synergistic effects of multi-kinase inhibition.

Conclusions. TOP1106 inhibits key kinases involved in inflammatory signalling pathways. Simultaneous inhibition of these kinases with TOP1106 leads to an improved anti-inflammatory profile compared to selective kinase inhibitors, highlighting the potential of NSKIs as a treatment for IBD.