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病中，tau神经病理 与痴呆症的严重程度相关。然而，对AD和AD相关痴呆(ADRD)的干预措施是 主要限于对不直接改变tau病理或由此产生的症状的治疗 神经变性，只有一种β导向的免疫疗法(ADUHELM)最近接受了一种有争议的 加快了疾病修改的审批。尽管针对其他Aβ的调查具有针对性 免疫治疗仍在继续，显然仍需要开发tau靶向的疾病修饰 治疗学。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。互变的MSUT2调制机制涉及MSUT2 CCCH结构域 与聚(A)RNA结合，因为CCCH结构域的缺失防止了动物模型的神经退变 紧张症。对100,000多种高多样性化合物的高通量筛选已经确定了许多有效剂量- 抑制MSUT2聚(A)RNA结合活性的响应性化合物，包括几类化合物 显示出良好的结构-活性关系。抑制作用的类药物小分子的鉴定 MSUT2与Poly(A)RNA的结合将提供一种干预相互作用的药理学手段。我们 假设MSUT2/聚(A)RNA结合的小分子抑制剂将减缓或逆转tau 病理学和病理性tau的毒性后果。这项建议的具体目标是优化 有效和特定的脑穿透MSUT2抑制剂，并用它们来演示概念验证治疗 紧张症的治疗方法。这些目标的成功实现将为未来的翻译工作奠定基础 通过生成MSUT2特异性工具化合物和进一步验证新的治疗靶点来进行研究 三叉神经症的药物干预。

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.