compound 76 [PMID: 28657314]   Click here for help

GtoPdb Ligand ID: 9609

Immunopharmacology Ligand
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.
2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 8
Hydrogen bond donors 1
Rotatable bonds 16
Topological polar surface area 146.3
Molecular weight 576.25
XLogP 7.29
No. Lipinski's rules broken 2
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Canonical SMILES CCOC(=O)c1cccc(c1)NC(=O)CCCCCCCSc1nnc(n1C)Cc1nn(C)c(=O)c2c1cccc2
Isomeric SMILES CCOC(=O)c1cccc(c1)NC(=O)CCCCCCCSc1nnc(n1C)Cc1nn(C)c(=O)c2c1cccc2
InChI InChI=1S/C30H36N6O4S/c1-4-40-29(39)21-13-12-14-22(19-21)31-27(37)17-8-6-5-7-11-18-41-30-33-32-26(35(30)2)20-25-23-15-9-10-16-24(23)28(38)36(3)34-25/h9-10,12-16,19H,4-8,11,17-18,20H2,1-3H3,(H,31,37)
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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Target Sp. Type Action Value Parameter Concentration range (M) Reference
IL-15 Hs Antagonist Antagonist 4.7 pKd - 2
pKd 4.7 (Kd 2.18x10-5 M) [2]
Description: By SPR binding to the IL-15 superagonist RLI.