The relaxin hormone is involved in the variety of biological functions in health and disease conditions. The role of relaxin is well-established in female reproduction and parturition, mammary gland and endometrial development, maintenance of myometrial quiescence during pregnancy. Relaxin signaling through its G protein-coupled receptor RXFP1 results in extracellular matrix remodeling through regulation of collagen deposition, cell invasiveness, proliferation and overall tissue homeostasis. Significantly, the therapeutic effects of relaxin in the treatment of renal, cardiac, skin, lung fibrosis, inflammation, and wound healing in animal models are well-established. Other data strongly indicate on the significance of relaxin in progression of prostate, breast, thyroid, endometrial and other cancers. Several clinical trials study the therapeutic role of relaxin in treatment of scleroderma, cervical ripening, fibromyalgia, orthodontics and as a protective agent in congestive heart failure. The easy and reliable indication of relaxin receptor activation in cells expressing RXFP1 is an increase of cAMP production. No chemical/small molecules or non-peptide agonists/antagonists are known for relaxin receptor. The current application is designed to fill this gap through high throughput small molecule agonist screening. Using HEK293T cells stably transfected with relaxin receptor we have optimized commercially available cAMP assay for a 1536-well plate format and performed trial screens of validation library. The assay is suitable for high throughput screening. After primary screen the active compounds will be selected in a series of secondary screens to identify specific relaxin receptor agonists. The discovery of relaxin agonists will provide basis for their use as anti-fibrotic, proliferative, vasodilatory, and angiogenic agents.
Relaxin is a peptide hormone with anti-fibrotic, angiogenic, vasodilatory, and cell-growth stimulating properties. The main goal of the application is to identify small molecule agonists of relaxin receptor.
| Wilson, Kenneth J; Xiao, Jingbo; Chen, Catherine Z et al. (2018) Optimization of the first small-molecule relaxin/insulin-like family peptide receptor (RXFP1) agonists: Activation results in an antifibrotic gene expression profile. Eur J Med Chem 156:79-92 |
| Agoulnik, Alexander I; Agoulnik, Irina U; Hu, Xin et al. (2017) Synthetic non-peptide low molecular weight agonists of the relaxin receptor 1. Br J Pharmacol 174:977-989 |
| Xiao, Jingbo; Huang, Zaohua; Chen, Catherine Z et al. (2013) Identification and optimization of small-molecule agonists of the human relaxin hormone receptor RXFP1. Nat Commun 4:1953 |
| Chen, Catherine Z; Southall, Noel; Xiao, Jingbo et al. (2013) Identification of small-molecule agonists of human relaxin family receptor 1 (RXFP1) by using a homogenous cell-based cAMP assay. J Biomol Screen 18:670-7 |
