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PDBsum entry 4qr4
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Transcription/transcription inhibitor
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PDB id
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4qr4
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References listed in PDB file
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Key reference
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Title
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Fragment-Based drug discovery of 2-Thiazolidinones as brd4 inhibitors: 2. Structure-Based optimization.
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Authors
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L.Zhao,
Y.Wang,
D.Cao,
T.Chen,
Q.Wang,
Y.Li,
Y.Xu,
N.Zhang,
X.Wang,
D.Chen,
L.Chen,
Y.L.Chen,
G.Xia,
Z.Shi,
Y.C.Liu,
Y.Lin,
Z.Miao,
J.Shen,
B.Xiong.
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Ref.
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J Med Chem, 2015,
58,
1281-1297.
[DOI no: ]
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PubMed id
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Abstract
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The signal transduction of acetylated histone can be processed through a
recognition module, bromodomain. Several inhibitors targeting BRD4, one of the
bromodomain members, are in clinical trials as anticancer drugs. Hereby, we
report our efforts on discovery and optimization of a new series of
2-thiazolidinones as BRD4 inhibitors along our previous study. In this work,
guided by crystal structure analysis, we reversed the sulfonamide group and
identified a new binding mode. A structure-activity relationship study on this
new series led to several potent BRD4 inhibitors with IC50 of about 0.05-0.1 μM
in FP binding assay and GI50 of 0.1-0.3 μM in cell based assays. To complete
the lead-like assessment of this series, we further checked its effects on BRD4
downstream protein c-Myc, investigated its selectivity among five different
bromodomain proteins, as well as the metabolic stability test, and reinforced
the utility of 2-thiazolidinone scaffold as BET bromodomain inhibitors in novel
anticancer drug development.
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