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Osteoporosis Screen for Praja1 E3 Ligase Inhibitors

Praja1 E3 连接酶抑制剂的骨质疏松症筛查

基本信息

批准号：
7420981
负责人：
Michael R Mattern
金额：
$ 41.75万
依托单位：
PROGENRA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-06-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7420981
关键词：
Aftercare Animal Model Award Biological Assay Biological Factors Bone Density Cell Line Cells Chemistry Collection Cultured Cells Developmental Therapeutics Program Eligibility Determination Evaluation Event Facility Construction Funding Category Fractionation Genetic Transcription Goals Health Human Lead Libraries Ligase Link Maintenance Marketing Measures Multiple Myeloma Nobel Prize Numbers Osteoblasts Osteogenesis Osteoporosis Paclitaxel Pathway interactions Pharmaceutical Preparations Phase Plant Extracts Plants Progress Reports Proteasome Inhibitor Purpose Quality of life Refractory Relapse Reporter Rosa Running Screening procedure Signal Transduction Source Specificity TP53 gene Techniques Technology Testing Therapeutic Agents Therapeutic Intervention Transcription Coactivator Ubiquitin Ubiquitin-Proteasomal Pathway Ubiquitination United States Food and Drug Administration Validation Velcade Work Yeasts aging population antitumor drug assay development base bone bone loss drug discovery high throughput screening inhibitor/antagonist marine organism multicatalytic endopeptidase complex mutant novel prevent programs small molecule therapy design ubiquitin-protein ligase

项目摘要

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).

描述（由申请人提供）：骨质疏松症仍然是老龄化人口中维持健康和生活质量的主要挑战。最有前途和最少利用的治疗干预措施是那些旨在增加骨密度的治疗方法。可操纵以实现这种合成代谢效果的目标的选择和验证取决于与骨形成相关的越来越多的信息。 Progenra 已经完成了 Praja1 检测的高通量筛选的构建和验证，Praja1 是一种 E3 连接酶，负责 Dlxin-1/MAGE-D1（转录激活剂 Dlx5 的共激活剂）的蛋白酶体降解。 Dlx5 与程序性骨形成相关。因此，推测这种 E3 连接酶的选择性抑制剂可以增加骨密度。将从 NCI 收集的小分子以及植物和海洋生物提取物进行筛选，以找到 Praja1 活性的有效和选择性抑制剂。将从命中中鉴定先导化合物，并通过测定指导活性提取物的分级分离，以确定活性成分。在这项工作产生的新型纯化合物中，将选择最好的化合物在培养细胞测定中评估它们对与骨形成相关的 Praja1 相关转录抑制的影响。通过筛选和二次测定评估的化合物将在第二阶段后考虑用于动物模型评估。骨质疏松症仍然是老龄化人口中维持健康和生活质量的重大挑战；最受追捧的治疗方法是那些能够增加骨量而不是仅仅防止进一步骨质流失的治疗方法。 Progenra 开发了一种技术，可以发现能够以这种方式发挥作用的化合物；该公司提议从植物和海洋生物的纯化合物和天然产物提取物中寻找新的骨质疏松症药物。后者在过去一直是高效药物（紫杉醇、他汀类药物等）的良好来源。