Characterizing the roles of novel soluble GSMs in AD pathology.

AD是一种神经退行性疾病，也是痴呆的主要原因。目前还没有治愈这种病的方法 毁灭性的混乱。阿尔茨海默病的病理特征有两个：β-淀粉样斑块 主要由一种小的蛋白质，淀粉样蛋白-β(Aβ)1-3和神经纤维缠结组成 过度磷酸化的tau蛋白。β是通过一系列切割淀粉样蛋白-β前体蛋白而产生的 (APP)通过β-和γ-分泌酶。易于聚集的Aβ42肽在AD病理和其他方面是必不可少的 与其他Aβ物种相比，在大脑β-淀粉样斑块中普遍存在。因此，我们专注于开发一种 可能优先降低Aβ42水平的化合物，是治疗AD的有效药物。我们发现 一类γ分泌酶调节剂(GSM)，是一组专门调节γ分泌酶的小分子 APP中的切割，从而优先降低Aβ42水平，而不改变其他γ分泌酶的切割 基材，例如凹槽。最近，我们合成了一类新的基于哒嗪的可溶性GSM(SGSM)，具有 具有很强的降低Aβ42水平和高水溶度的效力。到目前为止，我们最好的铅化合物是 SGSM15606，在降低Aβ42水平方面表现出突出的效力(在基于细胞的研究中，IC_(50)=7 nM)。它 还具有良好的药代动力学和药效学特性，包括良好的口服生物利用度， 端子半衰期长，间隙低。SGSM15606正在为一种研究新药做准备 能够进行IA期AD临床试验的应用程序(单次递增剂量)。现在有一百多个类似的 SGSM15606已经制成，尚未作为即将到来的临床试验的备份进行测试。我们 假设我们将能够表征这些分子对AD病理的影响，以确定 理想的复配比SGSM15606更有利。值得注意的是，我们的研究集中在疾病病理学上 临床前研究将提高候选分子在潜在临床试验中的成功。具体来说，我们 将首先使用二维(2D)AD单元模型来确定GSM15606和类似物的特征和优先顺序 优先降低Aβ42水平(目标1；1-2年)。然后我们将研究β上的优先化合物- 使用我们新的AD 3D人类神经细胞培养的淀粉样病理学和tau病理学(目标2；2-3年)。 最后，我们将确定可以急性和慢性减弱AD病理的顶级化合物 特征良好的AD转基因Tg2576小鼠(目标3；4-5年)。总体来说，建议的结果 研究不仅应该确定AD临床试验的最终化合物，而且还应该 加深对γ-分泌酶的生物学和AD发病机制的认识。

AD is a neurodegenerative disorder and the primary cause of dementia. Currently there is no cure for this devastating disorder. The pathology of AD is characterized by two distinctive hallmarks: the β-amyloid plaques primarily comprised of a small protein, amyloid-β (Aβ)1-3, and the neurofibrillary tangles composed of the hyperphosphorylated tau protein. Aβ is produced via a serial cleavage of the amyloid-β precursor protein (APP) through β- and γ-secretase. The aggregation-prone Aβ42 peptide is essential to AD pathology and more prevalent than other Aβ species in cerebral β-amyloid plaques. Thus, we have focused on developing a compound that may preferentially decrease Aβ42 levels and be an effective therapeutic for AD. We discovered a class of γ-secretase modulators (GSMs), a group of small molecules that specifically modulate γ-secretase cleavage in APP and thus preferentially lower Aβ42 levels without altering cleavage of other γ-secretase substrates, e.g. Notch. Recently, we generated a novel class of pyridazine-based soluble GSMs (SGSMs), with strong potency in lowering Aβ42 levels and high aqueous solubility. So far our best lead compound is SGSM15606, which displays outstanding potency in lowering Aβ42 levels (IC50 = 7 nM in cell-based studies). It also has excellent pharmacokinetics and pharmacodynamics properties including excellent oral bioavailability, long terminal half-life and low clearance. SGSM15606 is being prepared for an Investigational New Drug application enabling for a Phase-IA AD clinical trial (single ascending dose). Now over a hundred analogues of SGSM15606 have been made and have yet to be tested as backups for the forthcoming clinical trials. We hypothesize that we will be able to characterize the effects of these molecules on AD pathology to identify an ideal compound more favorable than SGSM15606. Notably, our studies focused on disease pathology in preclinical studies will enhance the success of candidate molecules in potential clinical trials. Specifically, we will first use two-dimensional (2D) AD cell models to characterize and prioritize GSM15606 and analogs that preferentially decrease Aβ42 levels (Aim 1; Years 1-2). We then will study the prioritized compounds on β- amyloid pathology and tau pathology using our novel 3D human neural cell cultures of AD (Aim 2; Years 2-3). Finally, we will identify the top compounds that can both acutely and chronically attenuate AD pathology using the well-characterized AD transgenic Tg2576 mice (Aim 3; Years 4-5). Collectively, the results of the proposed studies should not only identify the final and ultimate compound for an AD clinical trial, but also should enhance our understanding of the biology of γ-secretase and the pathogenesis of AD.