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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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PDB id:
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| Name: |
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Transcription
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Title:
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The first bromodomain of human brd4 in complex with 3,5 dimethylisoxaxole ligand
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Structure:
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Bromodomain-containing protein 4. Chain: a. Fragment: n-terminal bromodomain, residues 44-168. Synonym: brd4, protein hunk1. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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1.67Å
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R-factor:
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0.190
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R-free:
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0.220
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Authors:
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C.Chung,O.Mirguet,Y.Lamotte,P.Bamborough,D.Delannee,A.Bouillot, F.Gellibert,G.Krysa,A.Lewis,J.Witherington,P.Huet,Y.Dudit,L.Trottet, E.Nicodeme
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Key ref:
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O.Mirguet
et al.
(2014).
Naphthyridines as novel BET family bromodomain inhibitors.
Chemmedchem,
9,
580-589.
PubMed id:
DOI:
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Date:
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29-Jun-13
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Release date:
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11-Sep-13
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PROCHECK
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Headers
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References
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O60885
(BRD4_HUMAN) -
Bromodomain-containing protein 4 from Homo sapiens
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Seq:
Struc:
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1362 a.a.
127 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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DOI no:
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Chemmedchem
9:580-589
(2014)
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PubMed id:
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Naphthyridines as novel BET family bromodomain inhibitors.
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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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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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