PUBLICATION
Design, synthesis and biological evaluation of tyrosinase-targeting PROTACs
- Authors
- Fu, D., Yuan, Y., Qin, F., Xu, Y., Cui, X., Li, G., Yao, S., Deng, Y., Tang, Z.
- ID
- ZDB-PUB-211012-2
- Date
- 2021
- Source
- European Journal of Medicinal Chemistry 226: 113850 (Journal)
- Registered Authors
- Yao, Shaohua
- Keywords
- Cereblon E3 ubiquitin ligase, Human tyrosinase, PROTAC, Pigmentary skin disorders
- MeSH Terms
-
- Dose-Response Relationship, Drug
- Drug Design*
- Enzyme Inhibitors/chemical synthesis
- Enzyme Inhibitors/chemistry
- Enzyme Inhibitors/pharmacology*
- Humans
- Molecular Structure
- Monophenol Monooxygenase/antagonists & inhibitors*
- Monophenol Monooxygenase/metabolism
- Proteolysis/drug effects
- Pyrones/chemical synthesis
- Pyrones/chemistry
- Pyrones/pharmacology*
- Structure-Activity Relationship
- PubMed
- 34628235 Full text @ Eur. J. Med. Chem.
Citation
Fu, D., Yuan, Y., Qin, F., Xu, Y., Cui, X., Li, G., Yao, S., Deng, Y., Tang, Z. (2021) Design, synthesis and biological evaluation of tyrosinase-targeting PROTACs. European Journal of Medicinal Chemistry. 226:113850.
Abstract
The human tyrosinase is the most prominent therapeutic target for pigmentary skin disorders. However, the overwhelming majority efforts have been devoted to search mushroom tyrosinase inhibitors, which show poor inhibitory activity on human tyrosinase and certain side effects that cause skin damage in practical application. Herein, a series of degraders that directly targeted human tyrosinase was firstly designed and synthesized based on newly developed PROTAC technology. The best PROTAC TD9 induced human tyrosinase degradation obviously in dose and time-dependent manner, and its mechanism of inducing tyrosinase degradation has also been clearly demonstrated. Besides, encouraging results that low-toxicity PROTAC TD9 was applied to reduce zebrafish melanin synthesis have been obtained, highlighting the potential to treatment of tyrosinase-related disorders. Moreover, this work has innovatively expanded the application scope of PROTAC technology and laid a solid foundation for further development of novel drugs treating pigmentary skin disorders.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping