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PDBsum entry 5i80
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Transcription
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PDB id
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5i80
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References listed in PDB file
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Key reference
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Title
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Diving into the water: inducible binding conformations for brd4, Taf1(2), Brd9, And cecr2 bromodomains.
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Authors
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T.D.Crawford,
V.Tsui,
E.M.Flynn,
S.Wang,
A.M.Taylor,
A.Côté,
J.E.Audia,
M.H.Beresini,
D.J.Burdick,
R.Cummings,
L.A.Dakin,
M.Duplessis,
A.C.Good,
M.C.Hewitt,
H.R.Huang,
H.Jayaram,
J.R.Kiefer,
Y.Jiang,
J.Murray,
C.G.Nasveschuk,
E.Pardo,
F.Poy,
F.A.Romero,
Y.Tang,
J.Wang,
Z.Xu,
L.E.Zawadzke,
X.Zhu,
B.K.Albrecht,
S.R.Magnuson,
S.Bellon,
A.G.Cochran.
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Ref.
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J Med Chem, 2016,
59,
5391-5402.
[DOI no: ]
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PubMed id
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Abstract
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The biological role played by non-BET bromodomains remains poorly understood,
and it is therefore imperative to identify potent and highly selective
inhibitors to effectively explore the biology of individual bromodomain
proteins. A ligand-efficient nonselective bromodomain inhibitor was identified
from a 6-methyl pyrrolopyridone fragment. Small hydrophobic substituents
replacing the N-methyl group were designed directing toward the conserved
bromodomain water pocket, and two distinct binding conformations were then
observed. The substituents either directly displaced and rearranged the
conserved solvent network, as in BRD4(1) and TAF1(2), or induced a narrow
hydrophobic channel adjacent to the lipophilic shelf, as in BRD9 and CECR2. The
preference of distinct substituents for individual bromodomains provided
selectivity handles useful for future lead optimization efforts for selective
BRD9, CECR2, and TAF1(2) inhibitors.
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