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PDBsum entry 4yh4
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Protein binding
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PDB id
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4yh4
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References listed in PDB file
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Key reference
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Title
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Discovery of a new chemical series of brd4(1) inhibitors using protein-Ligand docking and structure-Guided design.
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Authors
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B.C.Duffy,
S.Liu,
G.S.Martin,
R.Wang,
M.M.Hsia,
H.Zhao,
C.Guo,
M.Ellis,
J.F.Quinn,
O.A.Kharenko,
K.Norek,
E.M.Gesner,
P.R.Young,
K.G.Mclure,
G.S.Wagner,
D.Lakshminarasimhan,
A.White,
R.K.Suto,
H.C.Hansen,
D.B.Kitchen.
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Ref.
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Bioorg Med Chem Lett, 2015,
25,
2818-2823.
[DOI no: ]
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PubMed id
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Abstract
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Bromodomains are key transcriptional regulators that are thought to be druggable
epigenetic targets for cancer, inflammation, diabetes and cardiovascular
therapeutics. Of particular importance is the first of two bromodomains in
bromodomain containing 4 protein (BRD4(1)). Protein-ligand docking in BRD4(1)
was used to purchase a small, focused screening set of compounds possessing a
large variety of core structures. Within this set, a small number of weak hits
each contained a dihydroquinoxalinone ring system. We purchased other analogs
with this ring system and further validated the new hit series and obtained
improvement in binding inhibition. Limited exploration by new analog synthesis
showed that the binding inhibition in a FRET assay could be improved to the low
μM level making this new core a potential hit-to-lead series. Additionally, the
predicted geometries of the initial hit and an improved analog were confirmed by
X-ray co-crystallography with BRD4(1).
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