In search of a small molecule agonist of the relaxin receptor RXFP1 for the treatment of liver fibrosis View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-12

AUTHORS

Andrew McBride, Anna M. Hoy, Mark J. Bamford, Danuta E. Mossakowska, Martin P. Ruediger, Jeremy Griggs, Sapna Desai, Kate Simpson, Ivan Caballero-Hernandez, John P. Iredale, Theresa Pell, Rebecca L. Aucott, Duncan S. Holmes, Scott P. Webster, Jonathan A. Fallowfield

ABSTRACT

The peptide hormone human relaxin-2 (H2-RLX) has emerged as a potential therapy for cardiovascular and fibrotic diseases, but its short in vivo half-life is an obstacle to long-term administration. The discovery of ML290 demonstrated that it is possible to identify small molecule agonists of the cognate G-protein coupled receptor for H2-RLX (relaxin family peptide receptor-1 (RXFP1)). In our efforts to generate a new medicine for liver fibrosis, we sought to identify improved small molecule functional mimetics of H2-RLX with selective, full agonist or positive allosteric modulator activity against RXFP1. First, we confirmed expression of RXFP1 in human diseased liver. We developed a robust cellular cAMP reporter assay of RXFP1 signaling in HEK293 cells transiently expressing RXFP1. A high-throughput screen did not identify further specific agonists or positive allosteric modulators of RXFP1, affirming the low druggability of this receptor. As an alternative approach, we generated novel ML290 analogues and tested their activity in the HEK293-RXFP1 cAMP assay and the human hepatic cell line LX-2. Differences in activity of compounds on cAMP activation compared with changes in expression of fibrotic markers indicate the need to better understand cell- and tissue-specific signaling mechanisms and their disease-relevant phenotypes in order to enable drug discovery. More... »

PAGES

10806

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-017-10521-9

DOI

http://dx.doi.org/10.1038/s41598-017-10521-9

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1091465466

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28883402


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