Small molecule PROTACs in targeted therapy: An emerging strategy to induce protein degradation

• Published in: European journal of medicinal chemistry 2019-07, Vol.174, p.159-180
• Main Authors: Xi, Meiyang, Chen, Yi, Yang, Hongyu, Xu, Huiting, Du, Kui, Wu, Chunlei, Xu, Yanfei, Deng, Liping, Luo, Xiang, Yu, Lemao, Wu, Yonghua, Gao, Xiaozhong, Cai, Tao, Chen, Bin, Shen, Runpu, Sun, Haopeng
• Format: Article
• Language: English
• Subjects: Degradation; E3 ligase; PROTACs; Proteasome
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.04.036

Inhibitors and nucleic acid based techniques were two main approaches to interfere with protein signaling and respective cascade in the past. Until recently, a new class of small molecules named proteolysis-targeting chimeras (PROTACs) have emerged. Each contains a target warhead, a linker and an E3 ligand. These bifunctional molecules recruit E3 ligases and target specific proteins for degradation via the ubiquitin (Ub) proteasome system (UPS). The degradation provides several advantages over inhibition in potency, selectivity and drug resistance. Thus, a variety of small molecule PROTACs have been discovered so far. In this review, we summarize the biological mechanism, advantages and recent progress of PROTACs, trying to offer an outlook in development of drugs targeting degradation in future. [Display omitted] •This review summarizes recent advances in development of PROTACs.•A stable ternary complex mediates ubiquitination and proteasomal degradation.•The degradation provides several advantages over inhibition.•Four kinds of E3 ligases are successfully used in PROTACs to recruit substrates.