Targeting MSUT2 with small molecules to ameliorate pathological tau

摘要 在额颞叶变性、阿尔茨海默病（AD）和相关的tau蛋白病、tau蛋白神经病理学中， 与痴呆的严重程度相关。然而，对AD和AD相关痴呆（ADRD）的干预措施， 很大程度上限于治疗不直接改变tau病理学或其结果的症状 神经变性，只有一个Aβ定向免疫（Aduhelm）最近接受了有争议的 加快疾病改良的审批。尽管针对其他Aβ的调查 尽管免疫疗法仍在继续，但仍然明显需要开发tau靶向的疾病修饰药物。 治疗学我们的工作已经证明，MSUT 2控制神经元对tau毒性的易感性。 哺乳动物的大脑MSUT 2调节tau蛋白病的机制涉及MSUT 2 CCCH结构域 与多聚（A）RNA结合，因为CCCH结构域的缺失防止了动物模型中的神经变性。 tau蛋白病高通量筛选超过100，000种高多样性化合物，已鉴定出许多活性剂量- 抑制MSUT 2 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。药物样小分子抑制剂的鉴定 MSUT 2与poly（A）RNA的结合将提供干预tau蛋白病的药理学手段。我们 假设MSUT 2/poly（A）RNA结合的小分子抑制剂将减缓或逆转tau蛋白 病理学和病理性tau的毒性后果。该提案的具体目标是优化 有效和特异性的脑渗透MSUT 2抑制剂，并使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翻译奠定基础。 通过生成MSUT 2特异性工具化合物并进一步验证用于治疗MSUT 2的新治疗靶点， tau蛋白病病症的药理学干预。

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.