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 - Funding Information:
Funding for the authors’ research was sponsored in part by the National Natural Science Foundation of China, grant numbers 81922064 (to L.O.), 81874290 (to L.O.) and 81903502 (to J.Z.); the National Science and Technology Major Project of the Ministry of Science and Technology of China, grant number 2018ZX09735005 (to L.O.); the National Major Scientific and Technological Special Project for ‘Signficant New Drugs Development’, grant number 2018ZX09201018-021 (to L.O.); the Sichuan Science and Technology Program, grant number 2019YFS0003 (to L.O.); the Sichuan Science and Technology Program, grant number 2020YJ0091 (to J.L.); the China Postdoctoral Science Foundation, grant number 2020M673268 (to J.Z.); the U.S. National Institutes of Health (NIH), grant number 1RO1CA251698-01 (to C.-M.C.); and the Cancer Prevention and Research Institute of Texas (CPRIT), grant numbers RP180349 and RP190077 (to C.-M.C.).
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 -