First small-molecule PROTACs for G protein-coupled receptors: inducing α1A-adrenergic receptor degradation

• Main Authors: Zhenzhen Li (Author), Yuxing Lin (Author), Hui Song (Author), Xiaojun Qin (Author), Zhongxia Yu (Author), Zheng Zhang (Author), Gaopan Dong (Author), Xiang Li (Author), Xiaodong Shi (Author), Lupei Du (Author), Wei Zhao (Author), Minyong Li (Author)
• Format: Book
• Published: Elsevier, 2020-09-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Proteolysis targeting chimeras (PROTACs) are dual-functional hybrid molecules that can selectively recruit an E3 ubiquitin ligase to a target protein to direct the protein into the ubiquitin-proteasome system (UPS), thereby selectively reducing the target protein level by the ubiquitin-proteasome pathway. Nowadays, small-molecule PROTACs are gaining popularity as tools to degrade pathogenic protein. Herein, we present the first small-molecule PROTACs that can induce the α1A-adrenergic receptor (α1A-AR) degradation, which is also the first small-molecule PROTACs for G protein-coupled receptors (GPCRs) to our knowledge. These degradation inducers were developed through conjugation of known α1-adrenergic receptors (α1-ARs) inhibitor prazosin and cereblon (CRBN) ligand pomalidomide through the different linkers. The representative compound 9c is proved to inhibit the proliferation of PC-3 cells and result in tumor growth regression, which highlighted the potential of our study as a new therapeutic strategy for prostate cancer.

Item Description

2211-3835
10.1016/j.apsb.2020.01.014