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PDBsum entry 5eni
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Signaling protein
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PDB id
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5eni
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References listed in PDB file
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Key reference
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Title
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A poised fragment library enables rapid synthetic expansion yielding the first reported inhibitors of phip(2), An atypical bromodomain.
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Authors
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O.B.Cox,
T.Krojer,
P.Collins,
O.Monteiro,
R.Talon,
A.Bradley,
O.Fedorov,
J.Amin,
B.D.Marsden,
J.Spencer,
F.Von delft,
P.E.Brennan.
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Ref.
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Chem Sci, 2016,
7,
2322-2330.
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PubMed id
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Abstract
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Research into the chemical biology of bromodomains has been driven by the
development of acetyl-lysine mimetics. The ligands are typically anchored by
binding to a highly conserved asparagine residue. Atypical bromodomains, for
which the asparagine is mutated, have thus far proven elusive targets, including
PHIP(2) whose parent protein, PHIP, has been linked to disease progression in
diabetes and cancers. The PHIP(2) binding site contains a threonine in place of
asparagine, and solution screening have yielded no convincing hits. We have
overcome this hurdle by combining the sensitivity of X-ray crystallography, used
as the primary fragment screen, with a strategy for rapid follow-up synthesis
using a chemically-poised fragment library, which allows hits to be readily
modified by parallel chemistry both peripherally and in the core. Our approach
yielded the first reported hit compounds of PHIP(2) with measurable
IC50 values by an AlphaScreen competition assay. The follow-up
libraries of four poised fragment hits improved potency into the sub-mM range
while showing good ligand efficiency and detailed structural data.
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