High-throughput screening campaign identifies a small molecule agonist of the relaxin family peptide receptor 4
AuthorLin, G-Y; Lin, L; Cai, X-Q; Dai, A-T; Zhu, Y; Li, J; Liu, Q; Yang, D-H; Bathgate, RAD; Wang, M-W
Source TitleActa Pharmacologica Sinica
PublisherNATURE PUBLISHING GROUP
University of Melbourne Author/sBathgate, Ross
AffiliationFlorey Department of Neuroscience and Mental Health
Document TypeJournal Article
CitationsLin, G. -Y., Lin, L., Cai, X. -Q., Dai, A. -T., Zhu, Y., Li, J., Liu, Q., Yang, D. -H., Bathgate, R. A. D. & Wang, M. -W. (2020). High-throughput screening campaign identifies a small molecule agonist of the relaxin family peptide receptor 4. ACTA PHARMACOLOGICA SINICA, 41 (10), pp.1328-1336. https://doi.org/10.1038/s41401-020-0390-x.
Access StatusAccess this item via the Open Access location
Open Access URLhttps://europepmc.org/articles/PMC7608467?pdf=render
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.
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