Chemical Probes as Allosteric Modulators of CK2 Alpha Prime Targeting Huntington's Disease

化学探针作为针对亨廷顿病的 CK2 Alpha Prime 变构调节剂

• 批准号: 10348753
• 负责人: Rocio Gomez-Pastor
• 金额: $ 18.94万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10348753
• 关键词: Address; Affect; Alleles; Allosteric Site; Animal Model; Binding; Binding Sites; Biological Assay; Brain; Calorimetry; Catalytic Domain; Cell Death; Cell model; Cessation of life; Chemicals; Clinic; Clinical Trials; Cognitive; Commerce; Corpus striatum structure; Data; Development; Disease; Energy Metabolism; Enzyme Inhibition; Enzymes; Excitatory Synapse; Exploratory/Developmental Grant; Family; Foundations; Funding; Future; Goals; Health; Healthcare Systems; Holoenzymes; Human; Huntington Disease; Impaired cognition; In Vitro; Inflammation; Intervention; Investments; Knockout Mice; Libraries; Ligands; Malignant Neoplasms; Medical; Molecular Chaperones; Motor; Nature; Neurodegenerative Disorders; Neurons; Outcome; Outcomes Research; Pathologic; Pathology; Patients; Phosphotransferases; Protein Isoforms; Proteins; Regulation; Research; Resources; Role; Stress; Structure-Activity Relationship; Surface Plasmon Resonance; Synapses; Testing; Therapeutic; Therapeutic Agents; Time; Titrations; Up-Regulation; Validation; Work; X-Ray Crystallography; analog; base; casein kinase II; density; heat shock transcription factor; high throughput screening; improved; in vitro Model; in vivo; inhibitor; kinase inhibitor; luminescence; motor behavior; mouse model; mutant; new therapeutic target; novel therapeutics; polyglutamine; prevent; programs; protein metabolism; small molecule; success; therapeutic development; therapeutic target; validation studies

PROJECT SUMMARY CK2α’, one of two catalytic subunits of human protein kinase CK2 holoenzyme, is inappropriately upregulated in cellular and animal models of Huntington’s disease (HD), and in human patients with HD. There are currently no selective inhibitors for CK2α’ available. Our work shows that CK2α’ is involved in the hyperphosphorylation and degradation of the stress protective Heat Shock transcription Factor 1 (HSF1). HSF1 has several protective roles in vivo, including regulation of stress protective chaperones and synaptic proteins, and energy metabolism. HSF1 levels are increased in an HD mouse model lacking one allele of CK2α’ (zQ175 HD), leading to increased chaperone expression and excitatory synapse density, decreased HTT aggregates and inflammation, and improved motor behavior. Given these exciting and promising results, we are initiating a program to identify selective allosteric inhibitors of CK2α’ that can serve as chemical probes for in vitro and in vivo target validation studies. The single specific aim of this exploratory project is to identify and characterize allosteric inhibitors of CK2α’ that can serve as leads for selective probe development. Herein, we propose to employ an ADP-GloTM luminescence high-throughput screen of the ChemDiv Allosteric Kinase Inhibitor (CDAKI) Library, increasing the likelihood that we will discover a small-molecule that binds allosterically to CK2α’. Active compounds will be further characterized by isothermal titration calorimetry (ITC) and x-ray crystallography. Confirmed active compounds will be validated using SAR (structure-activity relationship) by commerce. Our working hypothesis is that this library of known allosteric kinase inhibitors will generate excellent starting points for structurally-enabled compound development leading to selective allosteric probes. The potential impact of this project on human health is considerable. There is an unmet medical need for therapeutic agents that can halt or reverse the cognitive and motor decline associated with HD. This work will have a positive impact on the field as it will provide a path toward chemical probes for the validation of a new target for therapeutic development. The eventual development of a selective allosteric inhibitor of CK2α’ would address this unmet medical need and represent a significant advancement in the field of HD.

项目摘要 CK2α'是人类蛋白激酶CK2 Holoenzyme的两个催化亚基之一，在不适当地更新 亨廷顿氏病（HD）的细胞和动物模型以及HD患者。目前没有 可用的CK2α'选择性抑制剂。我们的工作表明CK2α'参与了高磷酸化和 应力保护热冲击转录因子1（HSF1）的降解。 HSF1具有多个受保护的角色 体内，包括调节应力保护的链酮和突触蛋白，以及能量代谢。 HSF1 在缺乏CK2α（ZQ175 HD）等位基因的HD小鼠模型中，水平升高，导致增加 伴侣表达和兴奋性突触密度，改善HTT聚集体和注射，以及 改善运动行为。鉴于这些令人兴奋和有希望的结果，我们将启动一个计划来识别 CK2α'的选择性变构抑制剂，可以用作体外和体内靶标的化学问题 研究。该探索性项目的一个具体目的是识别和表征 CK2α'可以用作选择性探针发展的铅。在此，我们建议使用ADP-GLOTM 化学变构激酶抑制剂（CDAKI）文库的发光高通量屏幕，增加了 我们会发现一种与CK2α结合的小分子的可能性。活性化合物将是 进一步的特征是等温滴定量热法（ITC）和X射线晶体学。确认活跃 通过商业使用SAR（结构活性关系）来验证化合物。我们的工作假设是 这个已知的变构激酶抑制剂的库将为结构启用的出色起点 复合发展导致选择性变构问题。该项目对人的潜在影响 健康是相当大的。对治疗剂的医疗需求未满足，可以停止或逆转 与高清相关的认知和运动下降。这项工作将对该领域产生积极影响，因为它将提供 验证治疗性开发目标的化学问题的道路。最终 开发CK2α'选择性变构抑制剂将满足这种未满足的医疗需求，并代表 高清领域的显着进步。