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PDBsum entry 4bw4
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Transcription
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PDB id
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4bw4
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References listed in PDB file
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Key reference
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Title
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Naphthyridines as novel bet family bromodomain inhibitors.
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Authors
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O.Mirguet,
Y.Lamotte,
C.W.Chung,
P.Bamborough,
D.Delannée,
A.Bouillot,
F.Gellibert,
G.Krysa,
A.Lewis,
J.Witherington,
P.Huet,
Y.Dudit,
L.Trottet,
E.Nicodeme.
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Ref.
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Chemmedchem, 2014,
9,
580-589.
[DOI no: ]
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PubMed id
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Abstract
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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.
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