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

Authors: Guang-yao Lin1,2,3, Lin Lin4, Xiao-qing Cai1, An-tao Dai1, Yue Zhu1,3, Jie Li1,3, Qing Liu1, De-hua Yang1,3, Ross A. D. Bathgate5, Ming-wei Wang1,2,3,4
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
Correspondence to: De-hua Yang:, Ross A. D. Bathgate:, Ming-wei Wang:,
DOI: 10.1038/s41401-020-0390-x
Received: 18 December 2019
Accepted: 21 February 2020
Advance online: 31 March 2020


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.
Keywords: RXFP4; INSL5; high-throughput screening; agonist; JK1

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