Chronic overproduction of IL-15 contributes to the pathogenesis of numerous inflammatory and autoimmune disorders. Experimental methods used to reduce the cytokine activity show promise as potential therapeutic approaches to modify IL-15 signaling and alleviate the development and progression of IL-15-related diseases. We previously demonstrated that an efficient reduction of IL-15 activity can be obtained by selective blocking of the specific, high affinity subunit alpha of the IL-15 receptor (IL-15Rα) with small-molecule inhibitors. In this study, we determined the structure-activity relationship of currently known IL-15Rα inhibitors in order to define the critical structural features required for their activity. To validate our predictions, we designed, analyzed in silico, and assessed in vitro function of 16 new potential IL-15Rα inhibitors. All newly synthesized molecules were benzoic acid derivatives with favorable ADME properties and they efficiently reduced IL-15 dependent peripheral blood mononuclear cells (PBMCs) proliferation, as well as TNF-α and IL-17 secretion. The rational design of IL-15 inhibitors may propel the identification of potential lead molecules for the development of safe and effective therapeutic agents.
Keywords: IL–15; IL–15Rα; benzoic acid; small–molecule IL–15Rα inhibitor.