Compound class:
Synthetic organic
Comment: This is the most potent compound developed via a pharmacophore and docking-based virtual screening campaign aimed at the discovery of small molecule inhibitors of the IL-15/IL-15R interaction [2]. Specifically, the investigators were searching for compounds that inhibit IL-15 binding to the IL-2Rβ subunit which together with the γ subunit, forms the signal transducing component of the IL-15R complex. Although the compound was found to be non-selective for IL-15 over IL-2, as a first in vitro SAR study it provides crucial information on the key binding interactions of IL-15 with its IL-2Rβ binding site, that will be useful for futher compound optimisation.
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Bioactivity Comments |
Compound 76 binds to IL-15 (specifically to an IL-15 superagonist called RLI that is a fusion protein linking IL-15 to the IL-15Rα sushi domain [1], used to exclude this interface from the analysis), and is biologically active as an inhibitor of IL-15-induced Stat5 phosphorylation (IC50 57nM) and IL-15-induced proliferation of 32Dβ cells which express IL-2Rβ/γ. Unfortunately it also inhibits IL-2 activity in the same assays (IC50 43nM for inhibition of IL-2-induced Stat5 phosphorylation), so is not selective for IL-15 activity. |
Selectivity at ligand targets | ||||||||||||||||||||||||||||||||||
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