4 years ago

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

Discovery of a Small-Molecule Inhibitor of Interleukin 15: Pharmacophore-Based Virtual Screening and Hit Optimization
Erwan Mortier, Romy Vomiandry, Laurence Arzel, Yannick Jacques, Jacques Lebreton, Benoit Sicard, Mike Maillasson, Didier Dubreuil, Agnès Quéméner, Monique Mathé-Allainmat
Interleukin (IL)-15 is a pleiotropic cytokine, which is structurally close to IL-2 and shares with it the IL-2 β and γ receptor (R) subunits. By promoting the activation and proliferation of NK, NK-T, and CD8+ T cells, IL-15 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/IL-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-15 to the IL-2Rβ 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.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00485

DOI: 10.1021/acs.jmedchem.7b00485

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