Small molecule agonists of the relaxin receptor

松弛素受体的小分子激动剂

• 批准号: 7758639
• 负责人: Alexander I Agoulnik
• 金额: $ 2.5万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7758639
• 关键词: 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

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：松弛素激素参与健康和疾病条件下的各种生物功能。松弛素在女性生殖和分娩、乳腺和子宫内膜发育、维持妊娠期子宫肌层静止中的作用已得到证实。松弛素信号通过其G蛋白偶联受体RXFP 1通过调节胶原沉积、细胞侵袭、增殖和整体组织稳态导致细胞外基质重塑。值得注意的是，松弛素在动物模型中治疗肾、心脏、皮肤、肺纤维化、炎症和伤口愈合的治疗效果已经得到充分证实。其他数据强烈表明松弛素在前列腺癌、乳腺癌、甲状腺癌、子宫内膜癌和其他癌症进展中的重要性。几项临床试验研究松弛素在治疗硬皮病、宫颈成熟、纤维肌痛、过敏和作为充血性心力衰竭的保护剂中的治疗作用。表达RXFP 1的细胞中松弛素受体活化的简单可靠的指示是cAMP产生的增加。对于松弛素受体，没有已知的化学/小分子或非肽激动剂/拮抗剂。目前的申请旨在通过高通量小分子激动剂筛选填补这一空白。使用松弛素受体稳定转染的HEK 293 T细胞，我们优化了1536孔板格式的市售cAMP测定，并对验证文库进行了试验筛选。该测定法适用于高通量筛选。初步筛选后，将在一系列二次筛选中选择活性化合物以鉴定特异性松弛素受体激动剂。松弛素激动剂的发现将为其作为抗纤维化、增殖、血管舒张和血管生成剂的应用提供基础。 公共卫生相关性：松弛素是一种肽类激素，具有抗纤维化、血管生成、血管扩张和细胞生长刺激特性。本申请的主要目的是鉴定松弛素受体的小分子激动剂。