Yang Wang, Xueyang Jiang, Feng Feng, Wenyuan Liu, Haopeng Sun. Degradation of proteins by PROTACs and other strategies[J]. Acta Pharmaceutica Sinica B, 2020, 10(2): 207-238

Degradation of proteins by PROTACs and other strategies
Yang Wanga, Xueyang Jiangd, Feng Fengc,d, Wenyuan Liua, Haopeng Sunb
a Department of Pharmaceutical Analysis, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China;
b Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China;
c Jiangsu Food and Pharmaceutical Science College, Huaian 223003, China;
d Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China
Abnormal protein expression or activities are associated with many diseases, especially cancer. Therefore, down-regulating the proteins involved in cancer cell survival proved to be an effective strategy for cancer treatmentda number of drugs based on proteolysis-targeting chimaera (PROTAC) mechanism have demonstrated clinical efficacy. Recent progress in the PROTAC strategy includes identification of the structure of the first ternary eutectic complex, extra-terminal domain-4-PROTAC-VonHippel-Lindau (BRD4-PROTAC-VHL), and PROTAC ARV-110 has entered clinical trials for the treatment of prostate cancer in 2019. These discoveries strongly proved the value of the PROTAC strategy. In this review, we summarize recent meaningful research of PROTACs, including the molecular design and optimization strategy as well as clinical application of candidate molecules. We hope to provide useful insights for rational design of PROTACs.
Key words:    Protein degradation    PROTAC    Ubiquitin proteasome system    E3 ubiquitin ligase    Target protein    Heterobifunctional molecule   
Received: 2019-05-20     Revised: 2019-07-19
DOI: 10.1016/j.apsb.2019.08.001
Funds: We gratefully thank the support from grants (Nos. 81573281) of National Natural Science Foundation of China. We also thank the support from Double First-Class initiative Innovation team project of China Pharmaceutical University (Nos. CPU2018GF11 and CPU2018GY34, China).
Corresponding author: Wenyuan Liu, Haopeng Sun;
Author description:
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Yang Wang
Xueyang Jiang
Feng Feng
Wenyuan Liu
Haopeng Sun

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