Discovery of a Small-Molecule Inhibitor of Interleukin 15: Pharmacophore-Based Virtual Screening and Hit Optimization
| Autor: | Yannick Jacques, Monique Mathé-Allainmat, Laurence Arzel, Mike Maillasson, Erwan Mortier, Jacques Lebreton, Romy Vomiandry, Didier Dubreuil, Agnès Quéméner, Benoit Sicard |
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| Přispěvatelé: | Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation (CEISAM), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), This work was funded by the programs CIMATH2 (Ciblage Moléculaire et Applications Thérapeutiques 2) and PIRAMID (Protein‐protein Interactions in Rational Approaches for Medicinal Innovative Drugs) supported by La Région Pays de la Loire. R.V. was supported by a fellowship from La Région Pays de la Loire. We thank CHEM)Symbiose and IMPACT facilities for technical assistance., Bernardo, Elizabeth, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Nantes (UN)-Université de Nantes (UN)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment [SDV.CAN]Life Sciences [q-bio]/Cancer 01 natural sciences Cell Line Small Molecule Libraries Mice Structure-Activity Relationship 03 medical and health sciences [SDV.CAN] Life Sciences [q-bio]/Cancer Drug Discovery medicine Animals Humans Receptor Cell Proliferation Interleukin-15 Virtual screening 010405 organic chemistry Chemistry Interleukin Stereoisomerism Triazoles Small molecule 0104 chemical sciences 3. Good health Cell biology Interleukin-2 Receptor beta Subunit Molecular Docking Simulation 030104 developmental biology Cytokine Interleukin 15 Immunology Phthalazines Molecular Medicine Pharmacophore Databases Chemical CD8 |
| Zdroj: | Journal of Medicinal Chemistry Journal of Medicinal Chemistry, American Chemical Society, 2017, 60 (14), pp.6249-6272. ⟨10.1021/acs.jmedchem.7b00485⟩ Journal of Medicinal Chemistry, 2017, 60 (14), pp.6249-6272. ⟨10.1021/acs.jmedchem.7b00485⟩ |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.7b00485 |
| Popis: | International audience; 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 and/or the proliferation of IL-15-dependent cells. One of them was selected as a hit, optimized by a structure-activity relationship approach, leading to the first small-molecule IL-15 inhibitor with sub-micromolar activity. |
| Databáze: | OpenAIRE |
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