Osteoporosis Screen for Praja1 E3 Ligase Inhibitors

描述（由申请人提供）：骨质疏松症仍然是老龄化人口维持健康和生活质量的主要挑战。其中最有希望和最少开发的治疗干预措施是那些旨在增加骨密度的治疗。选择和验证的目标，可以操纵，以实现这种合成代谢的影响取决于越来越多的信息有关骨形成。Progenra已经完成了Praja1高通量筛选试验的构建和验证，Praja1是一种E3连接酶，负责Dlxin-1/MAGE-D1的蛋白酶体降解，是转录激活剂Dlx5的辅助激活剂。Dlx5与程序性骨形成有关。因此，这种E3连接酶的选择性抑制剂被假设可以增加骨密度。将筛选来自NCI的小分子以及植物和海洋生物提取物，以找到有效和选择性的Praja1活性抑制剂。先导化合物将从hit中识别出来，活性提取物的分离将由测定法指导，以确定活性原理。在这项工作中产生的新型纯化合物中，将选择最佳化合物进行培养细胞试验，以评估其对praja1相关的骨形成相关转录抑制的影响。通过筛选和二级分析评估的化合物将在II期后考虑进行动物模型评估。骨质疏松症仍然是老龄化人口维持健康和生活质量的主要挑战；最受欢迎的治疗方法是那些能够增加骨量的方法，而不仅仅是防止进一步的骨质流失。Progenra已经开发了一种技术，可以发现可以以这种方式工作的化合物；该公司提议从植物和海洋生物的纯化合物和天然产品提取物中寻找新的骨质疏松症药物。后者在过去是高效药物的良好来源（紫杉醇，他汀类药物等）。

DESCRIPTION (provided by applicant): Osteoporosis remains a major challenge to the maintenance of health and quality of life in an aging population. Among the most promising and least exploited therapeutic interventions are those treatments designed to increase bone density. The selection and validation of targets that can be manipulated to achieve this anabolic effect depends on an increasing amount of information relating to bone formation. Progenra has completed the construction and validation for high throughput screening of an assay for Praja1, an E3 ligase responsible for proteasomal degradation of Dlxin-1/MAGE-D1, a coactivator of the transcriptional activator Dlx5. Dlx5 is associated with programmed bone formation. Thus, selective inhibitors of this E3 ligase are hypothesized to increase bone density. Collections of small molecules, as well as plant and marine organism extracts from the NCI, will be screened to find potent and selective inhibitors of Praja1 activity. Lead compounds will be identified from among the hits, and fractionation of active extracts will be guided by the assay, to identify active principles. Among the novel pure compounds arising from this effort, the best will be chosen for evaluation in cultured cell assays for their effects on Praja1-related inhibition of transcription associated with bone formation. Compounds that pass screening and secondary assay evaluation will be considered for animal model evaluation after Phase II. Osteoporosis remains a major challenge to the maintenance of health and quality of life in an aging population; the most sought after treatments are those which will build up bone mass instead of merely preventing further bone loss. Progenra has developed a technology that will permit the discovery of compounds that can work in this fashion; the company proposed to look for new osteoporosis drugs in collections of pure compounds and natural products extracts from plants and marine organisms. The latter have been good sources of highly effective drugs in the past (taxol, statins, etc).