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PDBsum entry 4hxr
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Protein binding/inhibitor
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PDB id
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4hxr
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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 inhibitors of the histone reader brd4 bromodomain.
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Authors
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L.Zhao,
D.Cao,
T.Chen,
Y.Wang,
Z.Miao,
Y.Xu,
W.Chen,
X.Wang,
Y.Li,
Z.Du,
B.Xiong,
J.Li,
C.Xu,
N.Zhang,
J.He,
J.Shen.
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Ref.
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J Med Chem, 2013,
56,
3833-3851.
[DOI no: ]
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PubMed id
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Abstract
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Recognizing acetyllysine of histone is a vital process of epigenetic regulation
that is mediated by a protein module called bromodomain. To contribute novel
scaffolds for developing into bromodomain inhibitors, we utilize a
fragment-based drug discovery approach. By successively applying docking and
X-ray crystallography, we were able to identify 9 fragment hits from diffracting
more than 60 crystals. In the present work, we described four of them and
carried out the integrated lead optimization for fragment 8, which bears a
2-thiazolidinone core. After several rounds of structure guided modifications,
we assessed the druggability of 2-thiazolidinone by modulating in vitro
pharmacokinetic studies and cellular activity assay. The results showed that two
potent compounds of 2-thiazolidinones have good metabolic stability. Also, the
cellular assay confirmed the activities of 2-thiazolidinones. Together, we hope
the identified 2-thiazolidinone chemotype and other fragment hits described
herein can stimulate researchers to develop more diversified bromodomain
inhibitors.
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