TY - JOUR
T1 - Targeting Bromodomain and Extraterminal Proteins for Drug Discovery
T2 - From Current Progress to Technological Development
AU - Tang, Pan
AU - Zhang, Jifa
AU - Liu, Jie
AU - Chiang, Cheng Ming
AU - Ouyang, Liang
N1 - Publisher Copyright:
© 2021 American Chemical Society.
PY - 2021/3/11
Y1 - 2021/3/11
N2 - Bromodomain and extraterminal (BET) proteins bind acetylated lysine residues in histones and nonhistone proteins via tandem bromodomains and regulate chromatin dynamics, cellular processes, and disease procession. Thus targeting BET proteins is a promising strategy for treating various diseases, especially malignant tumors and chronic inflammation. Many pan-BET small-molecule inhibitors have been described, and some of them are in clinical evaluation. Nevertheless, the limited clinical efficacy of the current BET inhibitors is also evident and has inspired the development of new technologies to improve their clinical outcomes and minimize unwanted side effects. In this Review, we summarize the latest protein characteristics and biological functions of BRD4 as an example of BET proteins, analyze the clinical development status and preclinical resistance mechanisms, and discuss recent advances in BRD4-selective inhibitors, dual-target BET inhibitors, proteolysis targeting chimera degraders, and protein-protein interaction inhibitors.
AB - Bromodomain and extraterminal (BET) proteins bind acetylated lysine residues in histones and nonhistone proteins via tandem bromodomains and regulate chromatin dynamics, cellular processes, and disease procession. Thus targeting BET proteins is a promising strategy for treating various diseases, especially malignant tumors and chronic inflammation. Many pan-BET small-molecule inhibitors have been described, and some of them are in clinical evaluation. Nevertheless, the limited clinical efficacy of the current BET inhibitors is also evident and has inspired the development of new technologies to improve their clinical outcomes and minimize unwanted side effects. In this Review, we summarize the latest protein characteristics and biological functions of BRD4 as an example of BET proteins, analyze the clinical development status and preclinical resistance mechanisms, and discuss recent advances in BRD4-selective inhibitors, dual-target BET inhibitors, proteolysis targeting chimera degraders, and protein-protein interaction inhibitors.
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U2 - 10.1021/acs.jmedchem.0c01487
DO - 10.1021/acs.jmedchem.0c01487
M3 - Review article
C2 - 33616410
AN - SCOPUS:85102905031
SN - 0022-2623
VL - 64
SP - 2419
EP - 2435
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 5
ER -