Triazol: a privileged scaffold for proteolysis targeting chimeras

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 a...

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Published in:Future medicinal chemistry 2019-11, Vol.11 (22), p.2919-2973
Main Authors: Xia, Li-Wen, Ba, Meng-Yu, Liu, Wei, Cheng, Weyland, Hu, Chao-Ping, Zhao, Qing, Yao, Yong-Fang, Sun, Mo-Ran, Duan, Yong-Tao
Format: Article
Language:English
Subjects:
drug development
PROTACs
protein degradation
Proteolysis
SAR
Structure-Activity Relationship
triazole
Triazoles - chemistry
Ubiquitination
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Summary: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.
ISSN:1756-8919
1756-8927
DOI:10.4155/fmc-2019-0159