Targeting MSUT2 with small molecules to ameliorate pathological tau

用小分子靶向 MSUT2 改善病理性 tau

• 批准号: 10735826
• 负责人: Brian C. Kraemer
• 金额: $ 218.13万
• 依托单位: SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735826
• 关键词: Acceleration; Aducanumab; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid; Amyloid beta-Protein; Animal Model; Binding; Biological; Biological Assay; Brain; Brain Diseases; Caenorhabditis elegans; Cells; Clinical Trials; Cognitive; Dementia; Deposition; Development; Diagnostic; Disease; Dose; Drug Kinetics; Evaluation; Exhibits; Frontotemporal Lobar Degenerations; Future; Goals; Human; Immunotherapeutic agent; Immunotherapy; Impaired cognition; Intervention; Investigation; Knock-out; Lesion; Libraries; Measurement; Measures; Memory; Metabolism; Modification; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Pathologic; Pathology; Penetration; Pharmaceutical Preparations; Pharmacodynamics; Phenotype; Poly(A)+ RNA; Predisposition; Property; Protein Isoforms; RNA Binding; RNA Recognition Motif; RNA-Binding Proteins; Risk; Safety; Severities; Structure-Activity Relationship; Tauopathies; Testing; Therapeutic; Toxic effect; Transgenic Mice; Validation; Work; analog; brain tissue; design; gene conservation; high throughput screening; in vivo; inhibitor; meetings; mouse model; neuroinflammation; neuropathology; neuroprotection; neurotoxicity; new therapeutic target; novel; pharmacokinetics and pharmacodynamics; pharmacologic; preservation; prevent; screening; small molecule; small molecule inhibitor; success; symptom treatment; targeted treatment; tau Proteins; tau aggregation; tau-1; therapeutic target; tool; translational study

Abstract In frontotemporal lobar degeneration, Alzheimer’s disease (AD) and related tauopathies, tau neuropathology correlates with severity of dementia. However, interventions for AD and AD related dementias (ADRDs) are largely limited to treatment of symptoms that do not directly alter tau pathology or the resultant neurodegeneration, with only one Aβ-directed immunotherapeutic (Aduhelm) recently receiving a controversial accelerated approval for disease modification. Although investigation into additional Aβ targeted immunotherapies continues, the obvious need remains for the development of tau-targeted disease-modifying therapeutics. Our work has demonstrated that MSUT2 controls neuronal susceptibility to tau toxicity in the mammalian brain. The mechanism of MSUT2 modulation of tauopathy involves the MSUT2 CCCH domain binding to poly(A) RNA, as deletion of the CCCH domain prevents neurodegeneration in animal models of tauopathy. High throughput screening of over 100,000 high diversity compounds has identified many active dose- responsive compounds that inhibit MSUT2 poly(A) RNA binding activity, including several classes of compounds exhibiting promising structure-activity relationships. The identification of drug-like small molecules that inhibit MSUT2 binding to poly(A) RNA will provide a pharmacological means of intervening against tauopathy. We hypothesize that small-molecule inhibitors of MSUT2/poly(A) RNA binding will slow or reverse tau pathology and the toxic consequences of pathological tau. The specific aims of this proposal are to optimize potent and specific brain-penetrant MSUT2 inhibitors and use them to demonstrate proof-of-concept therapeutic approaches to treating tauopathy. Successful completion of these aims will set the stage for future translational studies by both generating MSUT2 specific tool compounds and further validating a novel therapeutic target for pharmacological intervention in tauopathy disorders.

抽象的 在额颞叶变性中 与痴呆的严重程度相关。但是，AD和AD相关痴呆症（ADRD）的干预措施是 在很大程度上仅限于无法直接改变tau病理或结果的症状治疗 神经变性，只有一个Aβ导向的免疫治疗（Aduhelm）最近获得了有争议的 加速疾病修饰的批准。尽管研究了其他Aβ目标 免疫疗法仍在继续，明显的需求仍然需要开发tau靶向疾病改良的发展 疗法。我们的工作表明，MSUT2控制着神经元对TAU毒性的敏感性 哺乳动物的大脑。 MSUT2调制的Tauopathy的机制涉及MSUT2 CCCH域 与poly（a）RNA结合，因为CCCH结构域的缺失可防止在动物模型中的神经退行性 tauopathy。超过100,000种高多样性化合物的高吞吐量筛选已经确定了许多活跃的剂量 - 抑制MSUT2 poly（a）RNA结合活性的响应式化合物，包括几类化合物 表现出有希望的结构活动关系。鉴定抑制的药物样小分子 MSUT2与poly（a）RNA的结合将提供对抗tauopathy的介入的药物。我们 假设MSUT2/Poly（A）RNA结合的小分子抑制剂将减慢或反向Tau 病理学和病理tau的毒性后果。该提案的具体目的是优化 潜在和特定的脑渗透剂MSUT2抑制剂，并使用它们来证明概念验证治疗 治疗tauopathy的方法。这些目标的成功完成将为将来的翻译奠定舞台 通过生成MSUT2特定工具化合物的研究，并进一步验证了新的治疗靶标 陶氏病疾病的药理干预。