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PDBsum entry 5d3r
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Transcription
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PDB id
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5d3r
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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 pyrrole derivatives yield novel vectors for designing inhibitors of the acetyl-Lysine recognition site of brd4(1).
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Authors
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M.Hügle,
X.Lucas,
G.Weitzel,
D.Ostrovskyi,
B.Breit,
S.Gerhardt,
O.Einsle,
S.Günther,
D.Wohlwend.
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Ref.
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J Med Chem, 2016,
59,
1518-1530.
[DOI no: ]
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PubMed id
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Abstract
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Several human diseases, including cancer, show altered signaling pathways
resulting from changes in the activity levels of epigenetic modulators. In the
past few years, small-molecule inhibitors against specific modulators, including
the bromodomain and extra-terminal (BET) bromodomain family of acetylation
readers, have shown early promise in the treatment of the genetically defined
midline carcinoma and hematopoietic malignancies. We have recently developed a
novel potent inhibitor of BET proteins, 1 (XD14[ Angew. Chem., Int. Ed. 2013 ,
52 , 14055 ]), which exerts a strong inhibitory potential on the proliferation
of specific leukemia cell lines. In the study presented here, we designed
analogues of 1 to study the potential of substitutions on the 4-acyl pyrrole
backbone to occupy additional sites within the substrate recognition site of
BRD4(1). The compounds were profiled using ITC, DSF, and X-ray crystallography.
We could introduce several substitutions that address previously untargeted
areas of the substrate recognition site. This work may substantially contribute
to the development of therapeutics with increased target specificity against
BRD4-related malignancies.
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