Acta Pharmaceutica Sinica B

Acta Pharmaceutica Sinica B

Volume 10, Issue 9, September 2020, Pages 1669-1679
Acta Pharmaceutica Sinica B

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

https://doi.org/10.1016/j.apsb.2020.01.014Get rights and content
Under a Creative Commons license
open access

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 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.

Graphical abstract

Small-molecule proteolysis targeting chimeras (PROTACs) of α1A-adrenergic receptor (α1A-AR) were designed and synthesized through conjugation of known α1-ARs inhibitor prazosin and CRBN ligand pomalidomide through different linkers. Selected compounds displayed remarkable degradation activity. Inhibition of PC-3 cells proliferation and tumor growth regression of these compounds were investigated.

Image 1
  1. Download : Download high-res image (227KB)
  2. Download : Download full-size image

Key words

Small-molecule PROTACs
α1A-Adrenergic receptor
Ubiquitylation
Degradation
Prostate cancer

Abbreviations

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

Cited by (0)

Peer review under the responsibility of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences