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

  • Acta Pharmacol Sin. 2020 Oct;41(10):1328-1336. doi: 10.1038/s41401-020-0390-x.
Guang-Yao Lin  1  2  3 ,  Lin Lin  4 ,  Xiao-Qing Cai  1 ,  An-Tao Dai  1 ,  Yue Zhu  1  3 ,  Jie Li  1  3 ,  Qing Liu  1 ,  De-Hua Yang  5  6 ,  Ross A D Bathgate  7 ,  Ming-Wei Wang  8  9  10  11
Affiliations
  • 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. 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. [email protected].
  • 6. University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • 7. Florey Institute of Neuroscience and Mental Health, Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, VIC, 3052, Australia. [email protected].
  • 8. 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. [email protected].
  • 9. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. [email protected].
  • 10. University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • 11. School of Pharmacy, Fudan University, Shanghai, 201203, China. [email protected].
PMID: 32235863 DOI: 10.1038/s41401-020-0390-x
Abstract

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