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 asso...
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| Veröffentlicht in: | Journal of medicinal chemistry 2017-07, Vol.60 (14), p.6249-6272 |
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| container_title | Journal of medicinal chemistry |
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| creator | Quéméner, Agnès Maillasson, Mike Arzel, Laurence Sicard, Benoit Vomiandry, Romy Mortier, Erwan Dubreuil, Didier Jacques, Yannick Lebreton, Jacques Mathé-Allainmat, Monique |
| description | 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. |
| doi_str_mv | 10.1021/acs.jmedchem.7b00485 |
| format | Article |
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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.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.7b00485</identifier><identifier>PMID: 28657314</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Cancer ; Cell Line ; Cell Proliferation - drug effects ; Databases, Chemical ; Humans ; Interleukin-15 - antagonists & inhibitors ; Interleukin-15 - chemistry ; Interleukin-15 - metabolism ; Interleukin-2 Receptor beta Subunit - chemistry ; Interleukin-2 Receptor beta Subunit - metabolism ; Life Sciences ; Mice ; Molecular Docking Simulation ; Phthalazines - chemical synthesis ; Phthalazines - chemistry ; Phthalazines - pharmacology ; Small Molecule Libraries - chemistry ; Stereoisomerism ; Structure-Activity Relationship ; Triazoles - chemical synthesis ; Triazoles - chemistry ; Triazoles - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2017-07, Vol.60 (14), p.6249-6272</ispartof><rights>Copyright © 2017 American Chemical Society</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a451t-f95fac0177e294f5785a07d23b9bd73637c3dd2f5a87bc7f4807e12dd3e8de123</citedby><cites>FETCH-LOGICAL-a451t-f95fac0177e294f5785a07d23b9bd73637c3dd2f5a87bc7f4807e12dd3e8de123</cites><orcidid>0000-0002-4026-8496 ; 0000-0003-2603-8982 ; 0000-0001-9526-7880 ; 0000-0002-8848-0082 ; 0000-0002-6321-6488</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.7b00485$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.7b00485$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,315,781,785,886,2766,27078,27926,27927,56740,56790</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28657314$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://inserm.hal.science/inserm-01550121$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Quéméner, Agnès</creatorcontrib><creatorcontrib>Maillasson, Mike</creatorcontrib><creatorcontrib>Arzel, Laurence</creatorcontrib><creatorcontrib>Sicard, Benoit</creatorcontrib><creatorcontrib>Vomiandry, Romy</creatorcontrib><creatorcontrib>Mortier, Erwan</creatorcontrib><creatorcontrib>Dubreuil, Didier</creatorcontrib><creatorcontrib>Jacques, Yannick</creatorcontrib><creatorcontrib>Lebreton, Jacques</creatorcontrib><creatorcontrib>Mathé-Allainmat, Monique</creatorcontrib><title>Discovery of a Small-Molecule Inhibitor of Interleukin 15: Pharmacophore-Based Virtual Screening and Hit Optimization</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>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. 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| ispartof | Journal of medicinal chemistry, 2017-07, Vol.60 (14), p.6249-6272 |
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| subjects | Animals Cancer Cell Line Cell Proliferation - drug effects Databases, Chemical Humans Interleukin-15 - antagonists & inhibitors Interleukin-15 - chemistry Interleukin-15 - metabolism Interleukin-2 Receptor beta Subunit - chemistry Interleukin-2 Receptor beta Subunit - metabolism Life Sciences Mice Molecular Docking Simulation Phthalazines - chemical synthesis Phthalazines - chemistry Phthalazines - pharmacology Small Molecule Libraries - chemistry Stereoisomerism Structure-Activity Relationship Triazoles - chemical synthesis Triazoles - chemistry Triazoles - pharmacology |
| title | Discovery of a Small-Molecule Inhibitor of Interleukin 15: Pharmacophore-Based Virtual Screening and Hit Optimization |
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