First small-molecule PROTACs for G protein-coupled receptors: inducing α _1A-adrenergic receptor degradation

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.

Graphical abstract

Small-molecule proteolysis targeting chimeras (PROTACs) of α _1A-adrenergic receptor ( α _1A-AR) were designed and synthesized through conjugation of known α ₁-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.