Retinoid receptor subtype-selective modulators through synthetic modifications of RARγ agonists
| Autor: | Hinrich Gronemeyer, Pierre Germain, Harshal Khanwalkar, Géraldine Lemaire, Rosana Alvarez, Fátima Rodríguez-Barrios, Angel R. de Lera, Susana Alvarez |
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| Přispěvatelé: | Peney, Maité, Departamento de Química Orgánica, Universidade de Vigo, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2009 |
| Předmět: |
Models
Molecular Transcriptional Activation Agonist medicine.drug_class Recombinant Fusion Proteins MESH: Molecular Structure Clinical Biochemistry Pharmaceutical Science Retinoid receptor MESH: Carrier Proteins Retinoid X receptor Ligands Biochemistry Partial agonist Retinoids Transactivation Genes Reporter Drug Discovery MESH: Ligands MESH: Recombinant Fusion Proteins medicine Humans MESH: Retinoids Retinoid Molecular Biology Reporter gene MESH: Humans Molecular Structure Chemistry MESH: Genes Reporter Organic Chemistry Antagonist Cell biology MESH: Hela Cells Retinoid X Receptors MESH: Transcriptional Activation MESH: Retinoid X Receptors Molecular Medicine Carrier Proteins MESH: Models Molecular HeLa Cells |
| Zdroj: | Bioorganic and Medicinal Chemistry Bioorganic and Medicinal Chemistry, 2009, 17 (13), pp.4345-59. ⟨10.1016/j.bmc.2009.05.035⟩ |
| ISSN: | 0968-0896 1464-3391 |
| Popis: | International audience; A series of retinoids designed to interfere with the repositioning of H12 have been synthesized to identify novel RARgamma antagonists based on the structure of known RARgamma agonists. The transcriptional activities of the novel ligands were revealed by cell-based reporting assays, using engineered cells containg RAR subtype-selective fusions of the RAR ligand-binding domains with the yeast GAL4 activator DNA-binding domain and the cognate luciferase reporter gene. Whereas none of the ligands exhibited features of a selective RARgamma antagonist, some of them are endowed with interesting activities. In particular 24a acts as a pan-RAR agonist that induces at high concentration a higher transactivation potential on RARalpha than TTNPB and synergizes at low concentration with TTNPB-bound RARalpha but not RARbeta or RARgamma. Similarly, 24c synergizes with TTNPB-bound RARgamma and exhibits RARalpha,beta antagonist activity. Compounds 24b and 25b are strong RARalpha,beta-selective antagonists without agonist or antagonist activities for RARgamma. Compounds 24b and 24c display weak RXR antagonist activity. In addition several pan-antagonists and partial agonist/antagonists have been defined. |
| Databáze: | OpenAIRE |
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