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PDBsum entry 4o7a
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Transcription/inhibitor
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PDB id
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4o7a
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References listed in PDB file
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Key reference
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Title
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Acetyl-Lysine binding site of bromodomain-Containing protein 4 (brd4) interacts with diverse kinase inhibitors.
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Authors
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S.W.Ember,
J.Y.Zhu,
S.H.Olesen,
M.P.Martin,
A.Becker,
N.Berndt,
G.I.Georg,
E.Schönbrunn.
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Ref.
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Acs Chem Biol, 2014,
9,
1160-1171.
[DOI no: ]
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PubMed id
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Abstract
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Members of the bromodomain and extra terminal (BET) family of proteins are
essential for the recognition of acetylated lysine (KAc) residues in histones
and have emerged as promising drug targets in cancer, inflammation, and
contraception research. In co-crystallization screening campaigns using the
first bromodomain of BRD4 (BRD4-1) against kinase inhibitor libraries, we
identified and characterized 14 kinase inhibitors (10 distinct chemical
scaffolds) as ligands of the KAc binding site. Among these, the PLK1 inhibitor
BI2536 and the JAK2 inhibitor TG101209 displayed strongest inhibitory potential
against BRD4 (IC50 = 25 nM and 130 nM, respectively) and high selectivity for
BET bromodomains. Comparative structural analysis revealed markedly different
binding modes of kinase hinge-binding scaffolds in the KAc binding site,
suggesting that BET proteins are potential off-targets of diverse kinase
inhibitors. Combined, these findings provide a new structural framework for the
rational design of next-generation BET-selective and dual-activity BET-kinase
inhibitors.
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