High-throughput screening campaign identifies a small molecule agonist of the relaxin family peptide receptor 4  

作　　者：Guang-yao Lin Lin Lin Xiao-qing Cai An-tao Dai Yue Zhu Jie Li Qing Liu De-hua Yang Ross A.D.Bathgate Ming-wei Wang 

机构地区：[1]The National Center for Drug Screening and CAS Key Laboratory of Receptor Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences(CAS),Shanghai 201203,China [2]School of Life Science and Technology,ShanghaiTech University,Shanghai 201210,China [3]University of Chinese Academy of Sciences,Beijing 100049,China [4]School of Pharmacy,Fudan University,Shanghai 201203,China [5]Florey Institute of Neuroscience and Mental Health,Department of Biochemistry and Molecular Biology,The University of Melbourne,Parkville,VIC 3052,Australia

出　　处：《Acta Pharmacologica Sinica》2020年第10期1328-1336,共9页中国药理学报（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China 81872915(MWW),81573479(DHY),and 81773792(DHY);the National Science&Technology Major Project"Key New Drug Creation and Manufacturing Program" of China(2018ZX09735-001 to MWW,2018ZX09711002-002-005 to DHY and 2018ZX09711002-002-011 to QL);the National Key R&D Program of China 2018YFA0507000(MWW);the Novo Nordisk-CAS Research Fund(NNCAS-2017-1-CC to DHY)。

摘　　要：Relaxin/insulin-like family peptide receptor 4(RXFP4)is a class A G protein-coupled receptor(GPCR),and insulin-like peptide 5(INSL5)is its endogenous ligand.Although the precise physiological role of INSL5/RXFP4 remains elusive,a number of studies have suggested it to be a potential therapeutic target for obesity and other metabolic disorders.Since selective agonists of RXFP4 are scarcely available and peptidic analogs of INSL5 are hard to make,we conducted a high-throughput screening campaign against 52,000 synthetic and natural compounds targeting RXFP4.Of the 109 initial hits discovered,only 3 compounds were confirmed in secondary screening,with JK0621-D008 displaying the best agonism at human RXFP4.Its S-configuration stereoisomer(JK1)was subsequently isolated and validated by a series of bioassays,demonstrating a consistent agonistic effect in cells overexpressing RXFP4.This scaffold may provide a valuable tool to further explore the biological functions of RXFP4.

关 键 词：RXFP4 INSL5 high-throughput screening AGONIST JK1 

分 类 号：R96[医药卫生—药理学]