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、阿尔茨海默病 (AD) 和相关 tau 蛋白病中，tau 蛋白神经病理学 与痴呆症的严重程度相关。然而，针对 AD 和 AD 相关痴呆 (ADRD) 的干预措施尚不明确。 很大程度上限于治疗不直接改变 tau 病理学或由此产生的症状 神经退行性疾病，只有一种 Aβ 定向免疫治疗药物 (Aduhelm) 最近接受了有争议的治疗 加速批准疾病改造。尽管针对额外的 Aβ 进行了调查 免疫疗法仍在继续，显然仍然需要开发 tau 靶向疾病修饰药物 疗法。我们的工作表明 MSUT2 控制神经元对 tau 毒性的敏感性 哺乳动物的大脑。 MSUT2 调节 tau 蛋白病的机制涉及 MSUT2 CCCH 结构域 与 Poly(A) RNA 结合，因为 CCCH 结构域的删除可防止动物模型中的神经变性 tau蛋白病。对超过 100,000 种高多样性化合物的高通量筛选已鉴定出许多活性剂量- 抑制 MSUT2 poly(A) RNA 结合活性的响应性化合物，包括几类化合物 显示出有前景的结构-活性关系。抑制药物样小分子的鉴定 MSUT2 与 Poly(A) RNA 的结合将提供一种干预 tau 蛋白病的药理学方法。我们 假设 MSUT2/poly(A) RNA 结合的小分子抑制剂会减缓或逆转 tau 病理学和病理性 tau 蛋白的毒性后果。该提案的具体目标是优化 有效且特异性的脑渗透性 MSUT2 抑制剂，并用它们来证明概念验证治疗 治疗tau蛋白病的方法。这些目标的成功完成将为未来的转化奠定基础 通过生成 MSUT2 特定工具化合物并进一步验证新的治疗靶点进行研究 tau蛋白病疾病的药物干预。