1. Piperidinyl-embeded chalcones possessing anti PI3Kδ inhibitory properties exhibit anti-atopic properties in preclinical models
- Author
-
Charles Dumontet, Fabrice Gardebien, Guillaume Beck, Alessandra Nurisso, Eva-Laure Matera, Anne Tourette, Romain Haudecoeur, Doriane Mathe, Marine Peuchmaur, Grégory Bouchaud, Basile Pérès, Antoine Magnan, Ahcène Boumendjel, Guillaume Monneret, Justine Esmenjaud, Eve Mattei, Cédric Boyère, Université de Lyon (COMUE), Institut National de la Santé et de la Recherche Médicale (INSERM), Dynamique des Structures et Interactions des Macromolécules Biologiques - Pôle de La Réunion (DSIMB Réunion), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Grenoble Alpes (COMUE) (UGA), School of Pharmaceutical Sciences, Nanjing Tech University, Unité de recherche sur les Biopolymères, Interactions Assemblages (BIA), Institut National de la Recherche Agronomique (INRA), Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Labex ARCANE, and CBH-EUR-GS [ANR-17-EURE-0003]
- Subjects
0301 basic medicine ,Gene isoform ,Models, Molecular ,Chalcone ,Drug Evaluation, Preclinical ,Pharmacology ,Basophil degranulation ,Cell Degranulation ,Dermatitis, Atopic ,03 medical and health sciences ,chemistry.chemical_compound ,Route of administration ,Mice ,Phosphatidylinositol 3-Kinases ,Chalcones ,Piperidines ,Drug Discovery ,[SDV.IDA]Life Sciences [q-bio]/Food engineering ,medicine ,Animals ,Humans ,[SPI.GPROC]Engineering Sciences [physics]/Chemical and Process Engineering ,Allergic properties ,Protein Kinase Inhibitors ,PI3K delta ,Phosphoinositide-3 Kinase Inhibitors ,chemistry.chemical_classification ,Chemistry ,Organic Chemistry ,Degranulation ,General Medicine ,Atopic dermatitis ,medicine.disease ,Asthma ,3. Good health ,Basophils ,Disease Models, Animal ,030104 developmental biology ,Enzyme ,Anti-atopic activity ,Toxicity - Abstract
International audience; Phosphatidylinositide 3-kinases (PI3Ks) are widely expressed enzymes involved in membrane signalization pathways. Attempts to administer inhibitors with broad activity against different isoforms have failed due to toxicity. Conversely the PI3K delta isoform is much more selectively expressed, enabling therapeutic targeting of this isoform. Of particular interest PI3K delta is expressed in human basophils and its inhibition has been shown to reduce anti-IgE induced basophil degranulation, suggesting that PI3K delta inhibitors could be useful as anti-allergy drugs. Herein, we report for the first time the activity of compounds derived from chalcone scaffolds as inhibitors of normal human basophil degranulation and identified the most active compound with anti-PI3K delta properties that was investigated in preclinical models. Compound 18, namely 1-[2-hydroxy-4,6-dimethoxy-3-(N-methylpiperidin-4-yl)pheny1]-3(2,4,6-trimethoxypheny1)-prop-2-en-1-one, was found to inhibit normal human basophil degranulation in a dose-dependent manner. In a murine model of ovalbumin-induced asthma, compound 18 was shown to reduce expiratory pressure while its impact on the inflammatory infiltrate in alveolar lavage and total lung was dependent on the route of administration. In a DNFB-induced model of atopic dermatitis compound 18 administered systemically proved to be as potent as topical betamethasone. These results support the anti-atopic and allergic properties of the title compound and warrant further clinical development. (C) 2018 Elsevier Masson SAS
- Published
- 2018