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.

这个子项目是众多研究子项目之一