ARMET LIGANDS IN ANTI-CANCER DRUG DEVELOPMENT

抗癌药物开发中的 ARMET 配体

• 批准号: 8364919
• 负责人: Gerald R. Reeck
• 金额: $ 12.36万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8364919
• 关键词: ARMET gene; Animals; Antineoplastic Agents; Apoptosis; Binding; Cancer Center; Cells; Funding; Future; Gossypol; Grant; Human; Investigation; Kansas; Laboratories; Lead; Libraries; Ligand Binding; Ligands; Malignant - descriptor; National Center for Research Resources; Parents; Principal Investigator; Property; Proteins; Research; Research Infrastructure; Resources; Screening procedure; Source; Stress; Surface Plasmon Resonance; Technology; Therapeutic; United States National Institutes of Health; Universities; Validation; Variant; Work; cancer cell; chemical synthesis; cost; drug development; high throughput screening; instrument; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Armet is a bifunctional protein apparently present in all multicellular animals. Inside cells, Armet is a relatively unstudied and relatively recently component of the Unfolded Protein Response to ER stress, and it is this aspect of Armet that our work focuses on. We are working on human Armet as a target for drug development, using non-labelled screening to find tight binding ligands, followed by detailed binding studies of hits from the primary screening and studies of the effects of these selected compounds on cells. The rationale underlying this work is that the action of Armet as a part of the cell's machinery for dealing with ER stress, if interfered with by tight-binding ligands, would render cells more susceptible to the apoptosis, a typical result of ER stress, but a fate often circumvented by cancer cells. In the KU High Throughput Screening Laboratory, a validation library of 10,000 compounds, most of which are biologically active, was screened last spring against human Armet, as expressed and purified in my laboratory. We have a group of approximately 20 "hits" from that screen, several of which are under active investigation now in my laboratory at Kansas State University, with favorable results in that secondary analysis of binding to Armet. The current proposal has the following aims: to screen an additional 100,000 compounds at the KU HTS Lab, using an ICx Technology instrument that will soon arrive in that lab; to conduct detailed binding studies of selected ligands by Surface Plasmon Resonance (Biacore 3000 at KSU) and in one case (gossypol) binding of a set of variants of the parent compound; and to examine, both in the HTS Lab and at KSU, the effect of tightest binding ligands on human cells having a wide range of malignant properties, looking specifically for compound that render cancer cells vulnerable to apoptosis. This will lead, in turn, in future work, to synthesis of chemical variants of a lead compound or compounds, seeking tighter binding to Armet while retaining desired effects on cancer cells.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 外观是一种显然存在于所有多细胞动物中的双功能蛋白。内部电池内的装备是相对未研究的且相对较新的蛋白质反应对ER应力的组成部分，而我们的工作则是外套的这一方面。 我们正在使用非标记的筛选来找到紧密的结合配体，然后研究人类装备作为药物发育的靶标，然后进行了详细的结合研究，对主要筛选中的命中率进行了详细的结合研究以及这些所选化合物对细胞的影响的研究。 这项工作的基本原理是，如果通过紧密结合的配体干扰ER应力的电池机制的一部分，装备的作用将使细胞更容易受到凋亡的影响，这是ER胁迫的典型结果，但通常是由癌细胞支撑的。 在KU高吞吐量筛查实验室中，验证了10,000种化合物，其中大多数具有生物学活跃，去年春季筛选了我的实验室中的人类装备，并净化了人类装备。我们从该屏幕上有大约20个“命中”的组，其中一些人正在我在堪萨斯州立大学的实验室中进行了积极的研究，在二次结合与外观的二次分析中取得了良好的结果。 当前的提案具有以下目的：使用ICX技术仪器将很快到达该实验室的ICX技术工具，以筛选Ku HTS实验室的另外100,000种化合物；通过表面等离子体共振（KSU的BIACORE 3000）和一种情况下（Gossypol）结合，对父母化合物的一组变体进行详细的结合研究；为了检查HTS实验室和KSU，最紧密的结合配体对具有广泛恶性特性的人类细胞的影响，专门针对使癌细胞容易凋亡的化合物。 反过来，这将导致未来的工作中综合铅化合物或化合物的化学变异，从而寻求与装甲的更紧密结合，同时保留对癌细胞的期望作用。