2. Academic Validation
  3. First small-molecule PROTACs for G protein-coupled receptors: inducing α 1A-adrenergic receptor degradation

First small-molecule PROTACs for G protein-coupled receptors: inducing α 1A-adrenergic receptor degradation

  • Acta Pharm Sin B. 2020 Sep;10(9):1669-1679. doi: 10.1016/j.apsb.2020.01.014.
Zhenzhen Li 1,  Yuxing Lin 1,  Hui Song 2,  Xiaojun Qin 1,  Zhongxia Yu 2,  Zheng Zhang 1,  Gaopan Dong 1,  Xiang Li 1,  Xiaodong Shi 3,  Lupei Du 1,  Wei Zhao 2,  Minyong Li 1 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University, Jinan 250012, China.
  • 2 Department of Immunology, Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Shandong University, Jinan 250012, China.
  • 3 Department of Chemistry, University of South Florida, Tampa, FL 33620, USA.
  • 4 State Key Laboratory of Microbial Technology, Shandong University, Jinan 250100, China.
PMID: 33088687 DOI: 10.1016/j.apsb.2020.01.014
Abstract

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 α 1A-adrenergic receptor (α 1A-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 α 1-adrenergic receptors (α 1-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.

Keywords

BPH, benign prostatic hyperplasia; CRBN, cereblon; DCM, dichloromethane; DMF, dimethylformamide; DMSO, dimethylsulfoxide; Degradation; GPCR, G-protein-coupled receptor; HPLC, high-performance liquid chromatography; LUTS, lower urinary tract symptoms; PROTACs, proteolysis targeting chimeras; Prostate cancer; Small-molecule PROTACs; TEA, triethylamine; THF, tetrahydrofuran; Ubiquitylation; hPCE, human prostate cancer epithelial; α1-ARs, α1-adrenergic receptors; α1A-AR, α1A-adrenergic receptor; α1A-Adrenergic receptor; α1B-AR, α1B-adrenergic receptor; α1D-AR, α1D-adrenergic receptor.

Figures
Products