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PDBsum entry 6djc
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Transcription/inhibitor
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PDB id
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6djc
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References listed in PDB file
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Key reference
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Title
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Spatially constrained tandem bromodomain inhibition bolsters sustained repression of brd4 transcriptional activity for tnbc cell growth.
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Authors
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C.Ren,
G.Zhang,
F.Han,
S.Fu,
Y.Cao,
F.Zhang,
Q.Zhang,
J.Meslamani,
Y.Xu,
D.Ji,
L.Cao,
Q.Zhou,
K.L.Cheung,
R.Sharma,
N.Babault,
Z.Yi,
W.Zhang,
M.J.Walsh,
L.Zeng,
M.M.Zhou.
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Ref.
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Proc Natl Acad Sci U S A, 2018,
115,
7949-7954.
[DOI no: ]
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PubMed id
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Note: In the PDB file this reference is
annotated as "TO BE PUBLISHED". The citation details given above have
been manually determined.
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Abstract
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The importance of BET protein BRD4 in gene transcription is well recognized
through the study of chemical modulation of its characteristic tandem
bromodomain (BrD) binding to lysine-acetylated histones and transcription
factors. However, while monovalent inhibition of BRD4 by BET BrD inhibitors such
as JQ1 blocks growth of hematopoietic cancers, it is much less effective
generally in solid tumors. Here, we report a thienodiazepine-based bivalent BrD
inhibitor, MS645, that affords spatially constrained tandem BrD inhibition and
consequently sustained repression of BRD4 transcriptional activity in blocking
proliferation of solid-tumor cells including a panel of triple-negative breast
cancer (TNBC) cells. MS645 blocks BRD4 binding to transcription
enhancer/mediator proteins MED1 and YY1 with potency superior to monovalent BET
inhibitors, resulting in down-regulation of proinflammatory cytokines and genes
for cell-cycle control and DNA damage repair that are largely unaffected by
monovalent BrD inhibition. Our study suggests a therapeutic strategy to
maximally control BRD4 activity for rapid growth of solid-tumor TNBC cells.
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