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

作　　者：Zhenzhen Li Yuxing Lin Hui Song Xiaojun Qin Zhongxia Yu Zheng Zhang Gaopan Dong Xiang Li Xiaodong Shi Lupei Du Wei Zhao Minyong Li 

机构地区：[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

出　　处：《Acta Pharmaceutica Sinica B》2020年第9期1669-1679,共11页药学学报（英文版）

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)

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.

关 键 词：Small-molecule PROTACs α1A-Adrenergic receptor UBIQUITYLATION DEGRADATION Prostate cancer 

分 类 号：R914[医药卫生—药物化学]