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PDBsum entry 6e23
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Gene regulation/inhibitor
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PDB id
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6e23
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References listed in PDB file
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Key reference
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Title
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Displacement of wdr5 from chromatin by a win site inhibitor with picomolar affinity.
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Authors
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E.R.Aho,
J.Wang,
R.D.Gogliotti,
G.C.Howard,
J.Phan,
P.Acharya,
J.D.Macdonald,
K.Cheng,
S.L.Lorey,
B.Lu,
S.Wenzel,
A.M.Foshage,
J.Alvarado,
F.Wang,
J.G.Shaw,
B.Zhao,
A.M.Weissmiller,
L.R.Thomas,
C.R.Vakoc,
M.D.Hall,
S.W.Hiebert,
Q.Liu,
S.R.Stauffer,
S.W.Fesik,
W.P.Tansey.
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Ref.
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Cell Rep, 2019,
26,
2916.
[DOI no: ]
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PubMed id
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Abstract
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The chromatin-associated protein WDR5 is a promising target for pharmacological
inhibition in cancer. Drug discovery efforts center on the blockade of
the "WIN site" of WDR5, a well-defined pocket that is amenable to
small molecule inhibition. Various cancer contexts have been proposed to be
targets for WIN site inhibitors, but a lack of understanding of WDR5 target
genes and of the primary effects of WIN site inhibitors hampers their utility.
Here, by the discovery of potent WIN site inhibitors, we demonstrate that the
WIN site links WDR5 to chromatin at a small cohort of loci, including a specific
subset of ribosome protein genes. WIN site inhibitors rapidly displace WDR5 from
chromatin and decrease the expression of associated genes, causing translational
inhibition, nucleolar stress, and p53 induction. Our studies define a mode by
which WDR5 engages chromatin and forecast that WIN site blockade could have
utility against multiple cancer types.
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