ECE2017 Eposter Presentations: Interdisciplinary Endocrinology Cardiovascular Endocrinology and Lipid Metabolism (9 abstracts)
Therapeutic potentials of small molecular weight allosteric agonist of relaxin receptor
Alexander Agoulnik 1 , Irina Agoulnik 1 , Xin Hu 2 , Elena Kaftanovskaya 1 , Zaohua Huang 1 , Courtney Myhr 1 , Jingbo Xiao 2 , Mariluz Soula 1 , Brian Ho 1 , Elena Barnaeva 2 , Noel Southall 2 , Marc Ferrer 2 & Juan Marugan 2
1Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA; 2NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
The anti-fibrotic, vasodilatory, and angiogenic therapeutic properties of relaxin peptide have been shown in several animal models of human diseases and in clinical trials. Using high-throughput screening of small molecule library, structure-activity relationship (SAR) studies, ligand-receptor interaction modeling, site-specific mutagenesis, and transgenic animal studies we discovered the first series of small molecule agonists of relaxin GPCR, RXFP1. The lead compound ML290 is a selective RXFP1 agonist with low cytotoxicity, preferred in vitro ADME and in vivo pharmacokinetic properties. ML290 displays efficacy similar to the natural hormone in several functional assays in vitro. ML290 activates human, macaque, pig, and rabbit RXFP1, but not rodent receptors. Computational modeling of small molecule binding with human RXFP1 and related receptors in combination with site-directed receptor mutagenesis studies indicated that the small molecules activated RXFP1 through an allosteric site and did not compete with relaxin binding to RXFP1. To test agonist activity in vivo we produced mice with knock-in of human RXFP1 into mouse gene. The analysis of transgenic mice showed that the human receptor fully complement the deletion of mouse gene. Intravenous injection of relaxin led to a rapid increase in heart rate in unconscious WT and humanized mice, but not in Rxfp1 deficient animals. The ML290 injection increased heart rate in humanized but not in WT animals suggesting specific target engagement by small molecule agonist in vivo. Similar to relaxin IV injections of ML290 caused increased blood osmolality. Therapeutic potentials of the small molecular weight relaxin receptor agonist can be now tested in various preclinical cardiovascular and fibrotic models of human diseases.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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