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 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.