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Drug Discovery Targeting Bromodomain-Containing Protein 4
#MMPMID28195723
Liu Z
; Wang P
; Chen H
; Wold EA
; Tian B
; Brasier AR
; Zhou J
J Med Chem
2017[Jun]; 60
(11
): 4533-4558
PMID28195723
show ga
BRD4, the most extensively studied member of the BET family, is an epigenetic
regulator that localizes to DNA via binding to acetylated histones and controls
the expression of therapeutically important gene regulatory networks through the
recruitment of transcription factors to form mediator complexes, phosphorylating
RNA polymerase II, and by its intrinsic histone acetyltransferase activity.
Disrupting the protein-protein interactions between BRD4 and acetyl-lysine has
been shown to effectively block cell proliferation in cancer, cytokine production
in acute inflammation, and so forth. To date, significant efforts have been
devoted to the development of BRD4 inhibitors, and consequently, a dozen have
progressed to human clinical trials. Herein, we summarize the advances in drug
discovery and development of BRD4 inhibitors by focusing on their chemotypes, in
vitro and in vivo activity, selectivity, relevant mechanisms of action, and
therapeutic potential. Opportunities and challenges to achieve selective and
efficacious BRD4 inhibitors as a viable therapeutic strategy for human diseases
are also highlighted.
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