摘要
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 ubiquitinproteasome system(UPS),thereby selectively reducing the target protein level by the ubiquitinproteasome pathway.Nowadays,small-molecule PROTACs are gaining popularity as tools to desrade pathogenic protein.Herein,we present the first small-molecule PROTACs that can induce the alA-adrenergic receptor(α1 A-AR)degradation,which is also the first small-molecule PROTACs for G proteincoupled receptors(GPCRs)to our knowledge.These degradation inducers were developed through conjugation of knownα1-adrenergic receptors(α1-ARs)inhibitor prazosin and cereblon(CRBN)ligand pomalidomide through the different linkers.The representative compound 9 c 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.
基金
supported by grants from the National Natural Science Foundation of China(No.21629201)
the Shandong Natural Science Foundation(No.ZR2018ZC0233,China)
the Taishan Scholar Program at Shandong Province
the Qilu/Tang Scholar Program at Shandong University
the Major Project of Science and Technology of Shandong Province(No.2015ZDJS04001,China)
the Key Research and Development Project of Shandong Province(No.2017CXGC1401,China)
