Small molecule agonists of the relaxin receptor Grant

Small molecule agonists of the relaxin receptor .



abstract

  • 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. PUBLIC HEALTH RELEVANCE: 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.

date/time interval

  • September 1, 2009 - August 31, 2011

sponsor award ID

  • 1R03MH085705-01A1

local award ID

  • AWD000000000887

contributor

keywords

  • Adenylate Cyclase
  • Agonist
  • Animal Model
  • Binding
  • Biological
  • Biological Assay
  • Biological Process
  • Birth
  • Breast
  • Cardiac
  • Cell Line
  • Cells
  • Cervical Ripening
  • Chemicals
  • Clinical
  • Clinical Trials
  • Collagen
  • Congestive Heart Failure
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Data
  • Deposition
  • Development
  • Disease
  • Endometrial
  • Enzyme Immunoassay
  • Extracellular Matrix
  • Female
  • Fibromyalgia
  • Fibrosis
  • G Protein-Coupled Receptor Genes
  • G-Protein-Coupled Receptors
  • Goals
  • Health
  • Homeostasis
  • Hormone Receptor
  • Hormones
  • Human
  • Inflammation
  • Insulin Receptor
  • Investigation
  • Kidney
  • Laboratories
  • Leucine-Rich Repeat
  • Libraries
  • Lung
  • Maintenance
  • Malignant Neoplasms
  • Malignant neoplasm of prostate
  • Mammary gland
  • Modality
  • Monitor
  • Mutation
  • Myometrial
  • Normal tissue morphology
  • Organ
  • Orthodontics
  • Peptides
  • Pharmaceutical Preparations
  • Phase
  • Pre-Eclampsia
  • Pregnancy
  • Production
  • Property
  • Prostate
  • Protective Agents
  • Receptor Activation
  • Recombinants
  • Regulation
  • Relaxin
  • Reproduction
  • Role
  • Scleroderma
  • Screening procedure
  • Series
  • Signal Transduction
  • Signaling Protein
  • Skin
  • Therapeutic
  • Therapeutic Effect
  • Therapeutic Studies
  • Thyroid Gland
  • Tissues
  • Uterine Fibroids
  • Validation
  • Wound Healing
  • base
  • cell growth
  • cell motility
  • design
  • extracellular
  • fibrogenesis
  • high throughput screening
  • peptide hormone
  • pre-clinical
  • public health relevance
  • relaxin receptor
  • small molecule
  • tumor progression