Small molecule agonists of the relaxin receptor

描述(申请人提供)：松弛激素在健康和疾病条件下参与各种生物学功能。松弛素在女性生殖和分娩、乳腺和子宫内膜发育、妊娠期间维持子宫肌层静止等方面的作用是公认的。松弛素信号通过其G蛋白偶联受体RXFP1，通过调节胶原沉积、细胞侵袭、增殖和整体组织动态平衡，导致细胞外基质重塑。值得注意的是，在动物模型中，松弛素在治疗肾脏、心脏、皮肤、肺纤维化、炎症和伤口愈合方面的疗效是公认的。其他数据有力地表明了松弛素在前列腺癌、乳腺癌、甲状腺癌、子宫内膜癌和其他癌症进展中的重要性。几项临床试验研究了松弛素在治疗硬皮病、宫颈成熟、纤维肌痛、正畸以及作为充血性心力衰竭的保护剂方面的治疗作用。在表达RXFP1的细胞中，松弛素受体激活的简单和可靠的迹象是cAMP产生的增加。目前还没有已知的化学/小分子或非肽类激动剂/拮抗剂具有松弛素受体。目前的应用旨在通过高通量小分子激动剂筛选来填补这一空白。利用稳定转染松弛蛋白受体的HEK293T细胞，我们优化了商品化的1536孔板形式的cAMP分析，并对验证文库进行了初步筛选。该方法适用于高通量筛选。初筛后，活性化合物将在一系列二次筛选中被选择，以鉴定特定的松弛素受体激动剂。松弛素激动剂的发现将为其作为抗纤维化、增殖、血管扩张和血管生成药物的使用提供基础。 与公众健康相关：松弛素是一种多肽激素，具有抗纤维化、血管生成、血管扩张和刺激细胞生长的特性。该应用的主要目的是鉴定松弛素受体的小分子激动剂。

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.