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

  • J Med Chem. 2017 Jul 27;60(14):6249-6272. doi: 10.1021/acs.jmedchem.7b00485.
Agnès Quéméner  1 ,  Mike Maillasson  1 ,  Laurence Arzel  2 ,  Benoit Sicard  2 ,  Romy Vomiandry  1  2 ,  Erwan Mortier  1 ,  Didier Dubreuil  2 ,  Yannick Jacques  1 ,  Jacques Lebreton  2 ,  Monique Mathé-Allainmat  2
Affiliations
  • 1. CRCINA, INSERM, CNRS, University of Nantes , Nantes 44007, France.
  • 2. CEISAM, CNRS, Faculty of Sciences, University of Nantes , Nantes 44322, France.
PMID: 28657314 DOI: 10.1021/acs.jmedchem.7b00485
Abstract

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.

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