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PDBsum entry 4yk0
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References listed in PDB file
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Key reference
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Title
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Regulatory t cell modulation by cbp/ep300 bromodomain inhibition.
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Authors
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S.Ghosh,
A.Taylor,
M.Chin,
H.R.Huang,
A.R.Conery,
J.A.Mertz,
A.Salmeron,
P.J.Dakle,
D.Mele,
A.Cote,
H.Jayaram,
J.W.Setser,
F.Poy,
G.Hatzivassiliou,
D.Dealmeida-Nagata,
P.Sandy,
C.Hatton,
F.A.Romero,
E.Chiang,
T.Reimer,
T.Crawford,
E.Pardo,
V.G.Watson,
V.Tsui,
A.G.Cochran,
L.Zawadzke,
J.C.Harmange,
J.E.Audia,
B.M.Bryant,
R.T.Cummings,
S.R.Magnuson,
J.L.Grogan,
S.F.Bellon,
B.K.Albrecht,
R.J.Sims,
J.M.Lora.
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Ref.
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J Biol Chem, 2016,
291,
13014-13027.
[DOI no: ]
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PubMed id
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Abstract
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Covalent modification of histones is a fundamental mechanism of regulated gene
expression in eukaryotes, and interpretation of histone modifications is an
essential feature of epigenetic control. Bromodomains are specialized binding
modules that interact with acetylated histones, linking chromatin recognition to
gene transcription. Because of their ability to function in a domain-specific
fashion, selective disruption of bromodomain:acetylated histone interactions
with chemical probes serves as a powerful means for understanding biological
processes regulated by these chromatin adaptors. Here we describe the discovery
and characterization of potent and selective small molecule inhibitors for the
bromodomains of CREBBP/EP300 that engage their target in cellular assays. We use
these tools to demonstrate a critical role for CREBBP/EP300 bromodomains in
regulatory T cell biology. Because regulatory T cell recruitment to tumors is a
major mechanism of immune evasion by cancer cells, our data highlight the
importance of CREBBP/EP300 bromodomain inhibition as a novel, small
molecule-based approach for cancer immunotherapy.
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