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PDBsum entry 6sa3
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Transcription
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PDB id
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6sa3
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References listed in PDB file
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Key reference
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Title
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4-Acyl pyrroles as dual bet-Brd7/9 bromodomain inhibitors address beti insensitive human cancer cell lines.
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Authors
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M.Hügle,
P.Regenass,
R.Warstat,
M.Hau,
K.Schmidtkunz,
X.Lucas,
D.Wohlwend,
O.Einsle,
M.Jung,
B.Breit,
S.Günther.
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Ref.
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J Med Chem, 2020,
63,
15603-15620.
[DOI no: ]
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PubMed id
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Abstract
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Various malignant human diseases show disturbed signaling pathways due to
increased activity of proteins within the epigenetic machinery. Recently,
various novel inhibitors for epigenetic regulation have been introduced which
promise a great therapeutic benefit. Inhibitors for the bromo- and
extra-terminal domain (BET) family were of particular interest after inhibitors
had shown a strong antiproliferative effect. More recently, the focus has
increasingly shifted to bromodomains (BDs) outside the BET family. Based on
previously developed inhibitors, we have optimized a small series of 4-acyl
pyrroles, which we further analyzed by ITC, X-ray crystallography, selectivity
studies, the NCI60 cell-panel, and GI50 determinations for several
cancer cell lines. The inhibitors address both, BET and BRD7/9 BDs, with very
high affinity and show a strong antiproliferative effect on various cancer cell
lines that could not be observed for BD family selective inhibitors.
Furthermore, a synergistic effect on breast cancer (MCF-7) and melanoma
(SK-MEL-5) was proven.
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