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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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References listed in PDB file
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Key reference
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Title
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Optimization of 3,5-Dimethylisoxazole derivatives as potent bromodomain ligands.
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Authors
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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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Ref.
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J Med Chem, 2013,
56,
3217-3227.
[DOI no: ]
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PubMed id
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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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