TY - JOUR
T1 - Dual-target inhibitors of bromodomain and extra-terminal proteins in cancer
T2 - A review from medicinal chemistry perspectives
AU - Feng, Lu
AU - Wang, Guan
AU - Chen, Yi
AU - He, Gu
AU - Liu, Bo
AU - Liu, Jie
AU - Chiang, Cheng Ming
AU - Ouyang, Liang
N1 - Funding Information:
This study was supported by grants from National Natural Science Foundation of China (Grant nos. 81922064, 81874290, 81803755, and 91853109), Project of science and Technology Department of Sichuan Province (Grant no. 20YYJC3921), National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University (Grant no. Z20201004), US National Institutes of Health (NIH) (Grant nos. 1RO1CA251698‐01) and the Cancer Prevention and Research Institute of Texas (CPRIT) (Grant nos. RP180349 and RP190077).
Publisher Copyright:
© 2021 Wiley Periodicals LLC
PY - 2022/3
Y1 - 2022/3
N2 - Bromodomain-containing protein 4 (BRD4), as the most studied member of the bromodomain and extra-terminal (BET) family, is a chromatin reader protein interpreting epigenetic codes through binding to acetylated histones and non-histone proteins, thereby regulating diverse cellular processes including cell cycle, cell differentiation, and cell proliferation. As a promising drug target, BRD4 function is closely related to cancer, inflammation, cardiovascular disease, and liver fibrosis. Currently, clinical resistance to BET inhibitors has limited their applications but synergistic antitumor effects have been observed when used in combination with other tumor inhibitors targeting additional cellular components such as PLK1, HDAC, CDK, and PARP1. Therefore, designing dual-target inhibitors of BET bromodomains is a rational strategy in cancer treatment to increase potency and reduce drug resistance. This review summarizes the protein structures and biological functions of BRD4 and discusses recent advances of dual BET inhibitors from a medicinal chemistry perspective. We also discuss the current design and discovery strategies for dual BET inhibitors, providing insight into potential discovery of additional dual-target BET inhibitors.
AB - Bromodomain-containing protein 4 (BRD4), as the most studied member of the bromodomain and extra-terminal (BET) family, is a chromatin reader protein interpreting epigenetic codes through binding to acetylated histones and non-histone proteins, thereby regulating diverse cellular processes including cell cycle, cell differentiation, and cell proliferation. As a promising drug target, BRD4 function is closely related to cancer, inflammation, cardiovascular disease, and liver fibrosis. Currently, clinical resistance to BET inhibitors has limited their applications but synergistic antitumor effects have been observed when used in combination with other tumor inhibitors targeting additional cellular components such as PLK1, HDAC, CDK, and PARP1. Therefore, designing dual-target inhibitors of BET bromodomains is a rational strategy in cancer treatment to increase potency and reduce drug resistance. This review summarizes the protein structures and biological functions of BRD4 and discusses recent advances of dual BET inhibitors from a medicinal chemistry perspective. We also discuss the current design and discovery strategies for dual BET inhibitors, providing insight into potential discovery of additional dual-target BET inhibitors.
KW - bromodomain and extra-terminal (BET)
KW - bromodomain-containing protein 4
KW - dual-target inhibitors
KW - medicinal chemistry
KW - structure-activity relationship
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U2 - 10.1002/med.21859
DO - 10.1002/med.21859
M3 - Review article
C2 - 34633088
AN - SCOPUS:85116776747
SN - 0198-6325
VL - 42
SP - 710
EP - 743
JO - Medicinal Research Reviews
JF - Medicinal Research Reviews
IS - 2
ER -