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PDBsum entry 5fnu
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Transcription
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PDB id
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5fnu
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References listed in PDB file
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Key reference
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Title
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Monoacidic inhibitors of the kelch-Like ech-Associated protein 1: nuclear factor erythroid 2-Related factor 2 (keap1:nrf2) protein-Protein interaction with high cell potency identified by fragment-Based discovery.
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Authors
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T.G.Davies,
W.E.Wixted,
J.E.Coyle,
C.Griffiths-Jones,
K.Hearn,
R.Mcmenamin,
D.Norton,
S.J.Rich,
C.Richardson,
G.Saxty,
H.M.Willems,
A.J.Woolford,
J.E.Cottom,
J.P.Kou,
J.G.Yonchuk,
H.G.Feldser,
Y.Sanchez,
J.P.Foley,
B.J.Bolognese,
G.Logan,
P.L.Podolin,
H.Yan,
J.F.Callahan,
T.D.Heightman,
J.K.Kerns.
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Ref.
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J Med Chem, 2016,
59,
3991-4006.
[DOI no: ]
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PubMed id
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Abstract
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KEAP1 is the key regulator of the NRF2-mediated cytoprotective response, and
increasingly recognized as a target for diseases involving oxidative stress.
Pharmacological intervention has focused on molecules that decrease
NRF2-ubiquitination through covalent modification of KEAP1 cysteine residues,
but such electrophilic compounds lack selectivity and may be associated with
off-target toxicity. We report here the first use of a fragment-based approach
to directly target the KEAP1 Kelch-NRF2 interaction. X-ray crystallographic
screening identified three distinct "hot-spots" for fragment binding
within the NRF2 binding pocket of KEAP1, allowing progression of a weak fragment
hit to molecules with nanomolar affinity for KEAP1 while maintaining drug-like
properties. This work resulted in a promising lead compound which exhibits tight
and selective binding to KEAP1, and activates the NRF2 antioxidant response in
cellular and in vivo models, thereby providing a high quality chemical probe to
explore the therapeutic potential of disrupting the KEAP1-NRF2 interaction.
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