ORNAGOMETALLIC INHIBITORS FOR GLYCOGEN SYNTHASE KINASE 3BETA

糖原合成酶激酶 3BETA 的有机金属抑制剂

• 批准号: 7721290
• 负责人: DAVID W CHRISTIANSON
• 金额: $ 4.55万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7721290
• 关键词: Active Sites; Affinity; Anodes; Binding; Binding Sites; Cells; Collaborations; Colorectal Cancer; Complex; Computer Retrieval of Information on Scientific Projects Database; Data Set; Development; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Funding; Generations; Glycogen Synthase Kinase 3; Glycogen Synthase Kinases; Grant; Housing; Image; Institution; Laboratories; Lead; Ligands; Malignant neoplasm of prostate; Metals; Mutation; Protein Kinase; Purpose; Research; Research Personnel; Resolution; Resources; Roentgen Rays; Ruthenium; Side; Source; Structure; Time; United States National Institutes of Health; Work; X-Ray Crystallography; concept; design; detector; improved; inhibitor/antagonist; interest; melanoma; metal complex; mutant; three dimensional structure

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our laboratory focuses on the development of ruthenium complexes as kinetically inert enzyme inhibitors. In this concept, the metal center controls the orientation of the organic ligands to achieve unique three-dimensional structures that match the enzyme active site. X-ray crystallography of target enzymes with bound organoruthenium compounds are a central part of this effort. We recently developed nanomolar and even picomolar inhibitors for the glycogen synthase kinase-3beta (GSK-3beta). Co-crystal structural analyses of some organoruthenium complexes bound to Pim1 verify a binding in the ATP-binding site as designed (Angew. Chem. Int. Ed. 2006, 45, 1580). The protein kinases GSK-3 and Pim1 have been found to be related to prostate cancers, colorectal cancers, and melanoma, and their modulation is therefore of high interest. We are now especially interested in improving the affinity and selectivity of our lead structures for GSK-3. The functilnal groups in the active side that that are responsible for the potency and selectivity of the metal complexes will be investigated by introducing mutations in the active site of GSK-3. This work will include the following aim: Obtaining co-crystal structures of native and mutant GSK-3beta with the organoruthenium inhibitors: These structures will allow us to understand the binding mode in detail and to design second generation inhibitors for GSK-3. We already obtained cocrystals with one of the first generation compounds. These crystals did not diffract at the in-house X-Ray source (R axis IV++ image plate detector mounted on a Rigaku-200HB rotating anode X-ray generator, Christianson Lab). However, we were able to collect a complete data set at CHESS F1beamline (in collaboration with Dr. David Christiansons Lab). These crystals diffracted up to 3.1 ¿ and the unit cell parameters were determined. The purpose of this proposal is to request beam time to collect high-resolution data sets that will be obtained from crystals with better quality.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 我们的实验室专注于钌配合物作为动力学惰性酶抑制剂的发展。在这个概念中，金属中心控制有机配体的取向，以实现与酶活性位点相匹配的独特三维结构。结合有机钌化合物的目标酶的X射线晶体学是这一努力的核心部分。 我们最近开发了纳摩尔甚至皮摩尔的糖原合成酶激酶-3 β（GSK-3 β）抑制剂。与Pim 1结合的一些有机钌络合物的共晶体结构分析证实了如设计的ATP结合位点中的结合（Angew. Chem.Int.Ed.2006，45，1580）。已发现蛋白激酶GSK-3和Pim 1与前列腺癌、结肠直肠癌和黑色素瘤相关，因此它们的调节具有高度的兴趣。 我们现在特别感兴趣的是提高我们的先导结构对GSK-3的亲和力和选择性。将通过在GSK-3的活性位点中引入突变来研究活性侧中负责金属络合物的效力和选择性的官能团。这项工作将包括以下目标： 获得天然和突变GSK-3 β与有机钌抑制剂的共晶体结构：这些结构将使我们能够详细了解结合模式，并设计GSK-3的第二代抑制剂。我们已经获得了与第一代化合物之一的共晶。这些晶体在内部X射线源（安装在Rigaku-200HB旋转阳极X射线发生器上的R轴IV ++成像板探测器，Christianson Lab）下不起作用。然而，我们能够在CHESS F1光束线上收集完整的数据集（与大卫博士合作）。这些晶体衍射高达3.1英寸，并确定了晶胞参数。本提案的目的是要求束流时间，以收集高分辨率数据集，这些数据集将从质量更好的晶体中获得。