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Triazol: a privileged scaffold for proteolysis targeting chimeras

Li-Wen Xia

School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan 450001, China

Collaborative Innovation Center of Henan New Drug Research & Safety Evaluation, Zhengzhou, Henan 450001, China

Authors contributed equally

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,
Meng-Yu Ba

School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan 450001, China

Collaborative Innovation Center of Henan New Drug Research & Safety Evaluation, Zhengzhou, Henan 450001, China

Authors contributed equally

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,
Wei Liu

Henan Provincial Key Laboratory of Children's Genetics & Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou Children's Hospital, Zhengzhou University, Zhengzhou 450018, China

Authors contributed equally

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,
Weyland Cheng

Henan Provincial Key Laboratory of Children's Genetics & Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou Children's Hospital, Zhengzhou University, Zhengzhou 450018, China

,
Chao-Ping Hu

School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan 450001, China

Collaborative Innovation Center of Henan New Drug Research & Safety Evaluation, Zhengzhou, Henan 450001, China

,
Qing Zhao

School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan 450001, China

Collaborative Innovation Center of Henan New Drug Research & Safety Evaluation, Zhengzhou, Henan 450001, China

,
Yong-Fang Yao

***Author for correspondence:

E-mail Address: yongfangyao@zzu.edu.cn

School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan 450001, China

Collaborative Innovation Center of Henan New Drug Research & Safety Evaluation, Zhengzhou, Henan 450001, China

,
Mo-Ran Sun

**Author for correspondence:

E-mail Address: sunmr@zzu.edu.cn

School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan 450001, China

Collaborative Innovation Center of Henan New Drug Research & Safety Evaluation, Zhengzhou, Henan 450001, China

&
Yong-Tao Duan

*Author for correspondence:

E-mail Address: duanyongtao860409@163.com

Henan Provincial Key Laboratory of Children's Genetics & Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou Children's Hospital, Zhengzhou University, Zhengzhou 450018, China

Published Online:https://doi.org/10.4155/fmc-2019-0159

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.

Papers of special note have been highlighted as : • of interest

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