Triazol: A Privileged Scaffold for Proteolysis Targeting Chimeras

作者：Liwen Xia, Meng-Yu Ba, Wei Liu, Weyland Cheng, Chao-Ping Hu, Qing Zhao, Yongfang Yao, Moran Sun, Yongtao Duan · 发表于：Future Medicinal Chemistry · 年份：2019 · DOI：10.4155/fmc-2019-0159 · 被引用次数：44 · 研究领域：Protein Degradation and Inhibitors、Ubiquitin and proteasome pathways、Click Chemistry and Applications

Current traditional drugs such as enzyme inhibitors and receptor agonists/antagonists present inherent limitations due to occupancy-driven pharmacology as the mode of action. Proteolysis targeting chimeras (PROTACs) are composed of an E3 ligand, a connecting linker and a target protein ligand, and are an attractive approach to specifically knockdown-targeted proteins utilizing an event-driven mode of action. The length, hydrophilicity and rigidity of connecting linkers play important role in creating a successful PROTAC. Some PROTACs with a triazole linker have displayed promising anticancer activity. This review provides an overview of PROTACs with a triazole scaffold and discusses its structure–activity relationship. Important milestones in the development of PROTACs are addressed and a critical analysis of this drug discovery strategy is also presented.Graphical abstract is adapted with permission from Kymera Therapeutics; Figure 1 in Jarvis LM. Targeted protein degraders are redefining how small molecules look and act. C– 96(8) (2018) https://cen.acs.org/articles/96/i8/targeted-protein-degraders-are-redefining-how-small-molecules-look-and-act.html.