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
  • 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.
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