Abstract 17152: Identification of Cardiac Glycosides as Agonists of RXFP1 via Ultra High Throughput Screening
Introduction: Relaxin, a peptide hormone, has garnered much attention in the treatment of congestive heart failure based on its favorable hemodynamic profile. In the RELAX-AHF trial, serelaxin (a recombinant human protein) was shown to be effective in relieving subjective symptoms of dyspnea. Although at the time this was a secondary outcome, it provided a sustained 180-day mortality benefit in comparison to standard-of-care. The protein is administered as a 48-hour infusion at the time of presentation to a hospital setting for acute decompensated heart failure. There are very few small molecule agonists of RXFP1, the main relaxin receptor, being developed for oral administration.
Hypothesis: Can small molecule agonists of RXFP1 be identified by way of ultra high-throughput compound screening via phenotypic cell based assays?
Methods: Using a series of automated primary, secondary, and counter screening phenotypic cell based assays in conjunction with our >900,000 compound library, we identified compounds that signaled activation of RXFP1. Quantitative RT-PCR was used to support evidence of signal activation for identified compounds to RXFP1.
Results: The chemical scaffold of cardiac glycosides, such as digitoxin, was consistently identified in our screening assays. An antibody to Na/K ATPase was used in similar assays but failed to produce a signal response.
Conclusions: Cardiac glycosides appear to bind RXFP1. Further binding studies are needed to definitively prove this. This observation supports the notion that therapeutics such as digoxin may not only impart their effects by inhibition of Na/K ATPase but also by binding of RXFP1.
Author Disclosures: A. Bitar: None. S. Lee: None. M. Hull: None. L. Lairson: None. W. Shen: None. P.G. Schultz: None.
- © 2016 by American Heart Association, Inc.