2. Academic Validation
  3. Discovery of small molecule agonists of the Relaxin Family Peptide Receptor 2

Discovery of small molecule agonists of the Relaxin Family Peptide Receptor 2

  • Commun Biol. 2022 Nov 4;5(1):1183. doi: 10.1038/s42003-022-04143-9.
Maria Esteban-Lopez 1,  Kenneth J Wilson 2,  Courtney Myhr 1,  Elena M Kaftanovskaya 1,  Mark J Henderson 2,  Noel T Southall 2,  Xin Xu 2,  Amy Wang 2,  Xin Hu 2,  Elena Barnaeva 2,  Wenjuan Ye 2,  Emmett R George 2,  John T Sherrill 3,  Marc Ferrer 2,  Roy Morello 4,  Irina U Agoulnik 1 5,  Juan J Marugan 6,  Alexander I Agoulnik 7 8
Affiliations

Affiliations

  • 1 Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA.
  • 2 Early Translation Branch, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.
  • 3 Department of Orthopaedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
  • 4 Department of Physiology & Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
  • 5 Biomolecular Sciences Institute, Florida International University, Miami, FL, USA.
  • 6 Early Translation Branch, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA. [email protected].
  • 7 Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA. [email protected].
  • 8 Biomolecular Sciences Institute, Florida International University, Miami, FL, USA. [email protected].
PMID: 36333465 DOI: 10.1038/s42003-022-04143-9
Abstract

The relaxin/insulin-like family peptide receptor 2 (RXFP2) belongs to the family of class A G-protein coupled receptors (GPCRs) and it is the only known target for the insulin-like factor 3 peptide (INSL3). The importance of this ligand-receptor pair in the development of the gubernacular ligament during the transabdominal phase of testicular descent is well established. More recently, RXFP2 has been implicated in maintaining healthy bone formation. In this report, we describe the discovery of a small molecule series of RXFP2 agonists. These compounds are highly potent, efficacious, and selective RXFP2 allosteric agonists that induce gubernacular invagination in mouse embryos, increase mineralization activity in human osteoblasts in vitro, and improve bone trabecular parameters in adult mice. The described RXFP2 agonists are orally bioavailable and display favorable pharmacokinetic properties, which allow for future evaluation of the therapeutic benefits of modulating RXFP2 activation in disease models.

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