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Naphthyridines as Novel BET Family Bromodomain Inhibitors
Author(s) -
Mirguet Olivier,
Lamotte Yann,
Chung Chunwa,
Bamborough Paul,
Delannée Delphine,
Bouillot Anne,
Gellibert Françoise,
Krysa Gael,
Lewis Antonia,
Witherington Jason,
Huet Pascal,
Dudit Yann,
Trottet Lionel,
Nicodeme Edwige
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300259
Subject(s) - bromodomain , histone , bet inhibitor , chromatin , brd4 , acetylation , epigenetics , phd finger , chemistry , binding site , transcription (linguistics) , gene , computational biology , transcription factor , biology , biochemistry , linguistics , philosophy , zinc finger
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.