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PDBsum entry 4e96
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Protein binding/inhibitor
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PDB id
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4e96
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References listed in PDB file
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Key reference
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Title
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Identification of a chemical probe for bromo and extra c-Terminal bromodomain inhibition through optimization of a fragment-Derived hit.
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Authors
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P.V.Fish,
P.Filippakopoulos,
G.Bish,
P.E.Brennan,
M.E.Bunnage,
A.S.Cook,
O.Federov,
B.S.Gerstenberger,
H.Jones,
S.Knapp,
B.Marsden,
K.Nocka,
D.R.Owen,
M.Philpott,
S.Picaud,
M.J.Primiano,
M.J.Ralph,
N.Sciammetta,
J.D.Trzupek.
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Ref.
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J Med Chem, 2012,
55,
9831-9837.
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PubMed id
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Abstract
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The posttranslational modification of chromatin through acetylation at selected
histone lysine residues is governed by histone acetyltransferases (HATs) and
histone deacetylases (HDACs). The significance of this subset of the epigenetic
code is interrogated and interpreted by an acetyllysine-specific protein-protein
interaction with bromodomain reader modules. Selective inhibition of the bromo
and extra C-terminal domain (BET) family of bromodomains with a small molecule
is feasible, and this may represent an opportunity for disease intervention
through the recently disclosed antiproliferative and anti-inflammatory
properties of such inhibitors. Herein, we describe the discovery and
structure-activity relationship (SAR) of a novel, small-molecule chemical probe
for BET family inhibition that was identified through the application of
structure-based fragment assessment and optimization techniques. This has
yielded a potent, selective compound with cell-based activity (PFI-1) that may
further add to the understanding of BET family function within the bromodomains.
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