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PDBsum entry 4j0s
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Signaling protein
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PDB id
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4j0s
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PDB id:
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| Name: |
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Signaling protein
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Title:
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Crystal structure of the first bromodomain of human brd4 in complex with a 3,5-dimethylisoxazol ligand
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Structure:
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Bromodomain-containing protein 4. Chain: a. Fragment: unp residues 44-168. Synonym: protein hunk1. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: brd4, hunk1. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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1.84Å
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R-factor:
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0.163
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R-free:
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0.226
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Authors:
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P.Filippakopoulos,S.Picaud,J.Qi,I.Felletar,D.S.Hewings,F.Von Delft, S.J.Conway,C.Bountra,C.H.Arrowsmith,A.Edwards,S.Knapp,Structural Genomics Consortium (Sgc)
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Key ref:
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D.S.Hewings
et al.
(2013).
Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands.
J Med Chem,
56,
3217-3227.
PubMed id:
DOI:
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Date:
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31-Jan-13
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Release date:
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13-Feb-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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J Med Chem
56:3217-3227
(2013)
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PubMed id:
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Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands.
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D.S.Hewings,
O.Fedorov,
P.Filippakopoulos,
S.Martin,
S.Picaud,
A.Tumber,
C.Wells,
M.M.Olcina,
K.Freeman,
A.Gill,
A.J.Ritchie,
D.W.Sheppard,
A.J.Russell,
E.M.Hammond,
S.Knapp,
P.E.Brennan,
S.J.Conway.
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ABSTRACT
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The bromodomain protein module, which binds to acetylated lysine, is emerging as
an important epigenetic therapeutic target. We report the structure-guided
optimization of 3,5-dimethylisoxazole derivatives to develop potent inhibitors
of the BET (bromodomain and extra terminal domain) bromodomain family with good
ligand efficiency. X-ray crystal structures of the most potent compounds reveal
key interactions required for high affinity at BRD4(1). Cellular studies
demonstrate that the phenol and acetate derivatives of the lead compounds showed
strong antiproliferative effects on MV4;11 acute myeloid leukemia cells, as
shown for other BET bromodomain inhibitors and genetic BRD4 knockdown, whereas
the reported compounds showed no general cytotoxicity in other cancer cell lines
tested.
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Links
