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.

项目概要 CK2α’是人蛋白激酶 CK2 全酶的两个催化亚基之一，在 亨廷顿病 (HD) 的细胞和动物模型以及人类 HD 患者。目前没有 CK2α' 的选择性抑制剂可用。我们的工作表明 CK2α' 参与过度磷酸化和 应激保护性热休克转录因子 1 (HSF1) 的降解。 HSF1具有多种保护作用 体内，包括应激保护伴侣和突触蛋白的调节，以及能量代谢。 HSF1 在缺乏 CK2α' (zQ175 HD) 一个等位基因的 HD 小鼠模型中，该水平升高，导致 伴侣表达和兴奋性突触密度，减少 HTT 聚集和炎症，以及 改善运动行为。鉴于这些令人兴奋和有希望的结果，我们正在启动一项计划来确定 CK2α’的选择性变构抑制剂，可作为体外和体内靶标验证的化学探针 研究。该探索性项目的唯一具体目标是识别和表征变构抑制剂 CK2α’可作为选择性探针开发的先导化合物。在此，我们建议采用 ADP-Glo​​TM ChemDiv 变构激酶抑制剂 (CDAKI) 文库的发光高通量筛选，增加了 我们很可能会发现一种与 CK2α' 变构结合的小分子。活性化合物将是 通过等温滴定量热法 (ITC) 和 X 射线晶体学进一步表征。已确认活跃 商业部门将使用 SAR（结构-活性关系）对化合物进行验证。我们的工作假设是 该已知变构激酶抑制剂库将为结构启用提供良好的起点 导致选择性变构探针的化合物开发。该项目对人类的潜在影响 健康状况相当可观。对于能够阻止或逆转疾病的治疗药物的医疗需求尚未得到满足 与 HD 相关的认知和运动能力下降。这项工作将对该领域产生积极影响，因为它将提供 用于验证治疗开发新靶点的化学探针之路。最终的 开发 CK2α 的选择性变构抑制剂将解决这一未满足的医疗需求，并代表 高清领域取得重大进展。