Naphthyridines as novel BET family bromodomain inhibitors
| Autor: | Delphine Delannée, Pascal Huet, Chun-wa Chung, Anne Marie Jeanne Bouillot, Françoise Gellibert, Antonia J. Lewis, Yann Lamotte, Yann Dudit, Lionel Trottet, Jason Witherington, Olivier Mirguet, Edwige Nicodeme, Paul Bamborough, Gael Krysa |
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| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular Chromosomal Proteins Non-Histone Protein domain Biology Protein Serine-Threonine Kinases Crystallography X-Ray Biochemistry Histones Mice Structure-Activity Relationship Transcription (biology) Histone tails Drug Discovery Animals Acetylated histone General Pharmacology Toxicology and Pharmaceutics Naphthyridines Gene Protein Kinase Inhibitors Pharmacology Messenger RNA Mice Inbred BALB C Dose-Response Relationship Drug Molecular Structure Organic Chemistry Anti-Inflammatory Agents Non-Steroidal Nuclear Proteins Chromatin Bromodomain Protein Structure Tertiary Molecular Medicine Transcription Factors |
| Zdroj: | ChemMedChem. 9(3) |
| ISSN: | 1860-7187 |
| Popis: | Bromodomains (BRDs) are small protein domains found in a variety of proteins that recognize and bind to acetylated histone tails. This binding affects chromatin structure and facilitates the localisation of transcriptional complexes to specific genes, thereby regulating epigenetically controlled processes including gene transcription and mRNA elongation. Inhibitors of the bromodomain and extra-terminal (BET) proteins BRD2-4 and T, which prevent bromodomain binding to acetyl-modified histone tails, have shown therapeutic promise in several diseases. We report here the discovery of 1,5-naphthyridine derivatives as potent inhibitors of the BET bromodomain family with good cell activity and oral pharmacokinetic parameters. X-ray crystal structures of naphthyridine isomers have been solved and quantum mechanical calculations have been used to explain the higher affinity of the 1,5-isomer over the others. The best compounds were progressed in a mouse model of inflammation and exhibited dose-dependent anti-inflammatory pharmacology. |
| Databáze: | OpenAIRE |
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