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

文献类型：期刊论文

作者Lin, Guang-yao1,2,5,6; Lin, Lin3; Cai, Xiao-qing5,6; Dai, An-tao5,6; Zhu, Yue2,5,6; Li, Jie2,5,6; Liu, Qing5,6; Yang, De-hua2,5,6; Bathgate, Ross A. D.4; Wang, Ming-wei1,2,3,5,6
刊名ACTA PHARMACOLOGICA SINICA
出版日期2020-03-31
页码9
关键词RXFP4 INSL5 high-throughput screening agonist JK1
ISSN号1671-4083
DOI10.1038/s41401-020-0390-x
通讯作者Yang, De-hua(dhyang@simm.ac.cn) ; Bathgate, Ross A. D.(bathgate@florey.edu.au) ; Wang, Ming-wei(mwwang@simm.ac.cn)
英文摘要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.
WOS关键词PROTEIN-COUPLED RECEPTORS ; KINASE PATHWAY ; INSULIN ; INSL5
资助项目National Natural Science Foundation of China[81872915] ; National Natural Science Foundation of China[81573479] ; National Natural Science Foundation of China[81773792] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China[2018ZX09735-001] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China[2018ZX09711002-002-005] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China[2018ZX09711002-002-011] ; National Key R&D Program of China[2018YFA0507000] ; Novo Nordisk-CAS Research Fund[NNCAS-2017-1-CC] ; Victorian Government's Operational Infrastructure Support Program
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000522605300002
出版者NATURE PUBLISHING GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/280796]  
专题中国科学院上海药物研究所
通讯作者Yang, De-hua; Bathgate, Ross A. D.; Wang, Ming-wei
作者单位1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
4.Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Dept Biochem & Mol Biol, Parkville, Vic 3052, Australia
5.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
6.Chinese Acad Sci, CAS Key Lab Receptor Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Lin, Guang-yao,Lin, Lin,Cai, Xiao-qing,et al. High-throughput screening campaign identifies a small molecule agonist of the relaxin family peptide receptor 4[J]. ACTA PHARMACOLOGICA SINICA,2020:9.
APA Lin, Guang-yao.,Lin, Lin.,Cai, Xiao-qing.,Dai, An-tao.,Zhu, Yue.,...&Wang, Ming-wei.(2020).High-throughput screening campaign identifies a small molecule agonist of the relaxin family peptide receptor 4.ACTA PHARMACOLOGICA SINICA,9.
MLA Lin, Guang-yao,et al."High-throughput screening campaign identifies a small molecule agonist of the relaxin family peptide receptor 4".ACTA PHARMACOLOGICA SINICA (2020):9.

入库方式： OAI收割

来源：上海药物研究所

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