Discovery of a Small-Molecule Inhibitor of Interleukin 15: Pharmacophore-Based Virtual Screening and Hit Optimization

Interleukin (IL)-15 is a pleiotropic cytokine, which is structurally close to IL-2 and shares with it the IL-2 beta and gamma receptor (R) subunits. By promoting the activation and proliferation of NK, NK-T, and CD8+ T cells, IL-1.5 plays important roles in innate and adaptative immunity. Moreover, the association of high levels of IL-15 expression with inflammatory and autoimmune diseases has led to the development of various antagonistic approaches targeting IL-15. This study is an original approach aimed at discovering small-molecule inhibitors impeding IL-15/1L-15R interaction. A pharmacophore and docking based virtual screening of compound libraries led to the selection of 240 high-scoring compounds, 36 of which were found to bind IL-15, to inhibit the binding, of IL-1.5 to the IL-2R beta chain or the proliferation of IL-15-dependent cells or both. One of them was selected as a hit and optimized by a structure activity relationship approach, leading to the first small-molecule IL-15 inhibitor with sub-micromolar activity.