Characterizing the roles of novel soluble GSMs in AD pathology.

表征新型可溶性 GSM 在 AD 病理学中的作用。

• 批准号: 10316217
• 负责人: Can Martin Zhang
• 金额: $ 42.59万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10316217
• 关键词: 3-Dimensional; Academia; Acute; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease therapeutic; Amyloid beta-42; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animals; Attenuated; Biological Availability; Biology; Cell Culture Techniques; Cell model; Cells; Cerebrum; Chronic; Clinical; Clinical Trials; Cognition; Collaborations; Dementia; Disease; Dose; Elderly; Evaluation; Funding; Goals; Grant; Half-Life; Human; Investigational Drugs; Investigational New Drug Application; Lead; Mus; Mutation; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Oral; Parents; Pathogenesis; Pathology; Peptides; Pharmaceutical Preparations; Phase; Phase Ia Trial; Production; Property; Proteins; Pyridazines; Reporting; Role; Safety; Senile Plaques; Sodium Chloride; Solubility; Testing; Tg2576; Transgenic Organisms; United States National Institutes of Health; Water; Work; analog; aqueous; base; beta amyloid pathology; beta secretase; clinical candidate; familial Alzheimer disease; gamma secretase; hyperphosphorylated tau; improved; mouse model; notch protein; novel; pharmacokinetics and pharmacodynamics; preclinical study; small molecule; success; tau Proteins; tau-1; therapeutically effective; treatment duration; two-dimensional

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.

AD是一种神经退行性疾病，是痴呆的主要原因。目前还没有治愈的方法 毁灭性的混乱AD的病理学特征有两个独特的标志：β-淀粉样蛋白斑块 主要由一种小蛋白--β淀粉样蛋白（Aβ）1-3组成，神经元缠结由 过度磷酸化的tau蛋白。Aβ是通过淀粉样β前体蛋白的连续裂解产生的 (APP)通过β-和γ-分泌酶。聚集倾向Aβ42肽是AD病理学所必需的， 在脑β淀粉样斑块中比其他Aβ种类更普遍。因此，我们专注于开发一个 该化合物可以优先降低Aβ42水平，并且是AD的有效治疗剂。我们发现 一类γ-分泌酶调节剂（GSMs），一组特异性调节γ-分泌酶的小分子 APP裂解，从而优先降低Aβ42水平，而不改变其他γ-分泌酶的裂解 基底，例如Notch。最近，我们产生了一类新的基于哒嗪的可溶性GSM（SGSM）， 降低Aβ42水平的强效和高水溶性。目前为止我们最好的先导化合物是 SGSM 15606在降低Aβ42水平方面表现出出色的效力（在基于细胞的研究中，IC 50 = 7 nM）。它 还具有优良的药代动力学和药效学性质，包括优良的口服生物利用度， 终末半衰期长，清除率低。SGSM 15606正在为研究性新药进行准备 用于IA期AD临床试验（单次给药剂量递增）。现在有一百多个类似物 SGSM 15606已经制成，尚未作为即将进行的临床试验的备份进行测试。我们 假设我们将能够描述这些分子对AD病理学的影响，以确定 理想化合物比SGSM 15606更有利。值得注意的是，我们的研究集中在疾病病理学， 临床前研究将提高候选分子在潜在临床试验中的成功率。我们特别 将首先使用二维（2D）AD细胞模型来表征和优先考虑GSM 15606和类似物， 优先降低Aβ42水平（目标1;第1-2年）。然后，我们将研究β- 淀粉样蛋白病理学和tau病理学，使用我们的AD的新型3D人类神经细胞培养物（Aim 2;第2-3年）。 最后，我们将确定顶级化合物，可以急性和慢性衰减AD病理使用 特征良好的AD转基因Tg 2576小鼠（Aim 3;第4-5年）。总的来说，拟议的 研究不仅应该确定AD临床试验的最终和最终化合物，而且应该 增强我们对γ-分泌酶的生物学特性和AD发病机制的认识。

项目成果

Molecular imaging of Alzheimer's disease-related gamma-secretase in mice and nonhuman primates.

• DOI: 10.1084/jem.20182266
• 发表时间: 2020-12-07
• 期刊: The Journal of experimental medicine
• 作者: Xu Y;Wang C;Wey HY;Liang Y;Chen Z;Choi SH;Ran C;Rynearson KD;Bernales DR;Koegel RE;Fiedler SA;Striar R;Wagner SL;Tanzi RE;Zhang C
• 通讯作者: Zhang C

Upregulation of Alzheimer's Disease Amyloid-β Protein Precursor in Astrocytes Both in vitro and in vivo.

• DOI: 10.3233/jad-200128
• 发表时间: 2020
• 期刊: Journal of Alzheimer's disease : JAD
• 作者: Liang Y;Raven F;Ward JF;Zhen S;Zhang S;Sun H;Miller SJ;Choi SH;Tanzi RE;Zhang C
• 通讯作者: Zhang C

Mechanisms that synergistically regulate η-secretase processing of APP and Aη-α protein levels: relevance to pathogenesis and treatment of Alzheimer's disease.

协同调节 APP 和 Aβ-α 蛋白水平的 α-分泌酶加工的机制：与阿尔茨海默病的发病机制和治疗的相关性。

• 发表时间: 2017
• 期刊: Discovery medicine
• 影响因子: 1.4
• 作者: Ward,Joseph;Wang,Haizhi;Saunders,AleisterJ;Tanzi,RudolphE;Zhang,Can
• 通讯作者: Zhang,Can

Preclinical validation of a potent γ-secretase modulator for Alzheimer's disease prevention.

• DOI: 10.1084/jem.20202560
• 发表时间: 2021-04-05
• 期刊: The Journal of experimental medicine
• 作者: Rynearson KD;Ponnusamy M;Prikhodko O;Xie Y;Zhang C;Nguyen P;Hug B;Sawa M;Becker A;Spencer B;Florio J;Mante M;Salehi B;Arias C;Galasko D;Head BP;Johnson G;Lin JH;Duddy SK;Rissman RA;Mobley WC;Thinakaran G;Tanzi RE;Wagner SL
• 通讯作者: Wagner SL

Soluble Gamma-secretase Modulators Attenuate Alzheimer's β-amyloid Pathology and Induce Conformational Changes in Presenilin 1.

• DOI: 10.1016/j.ebiom.2017.08.028
• 发表时间: 2017-10
• 期刊: EBioMedicine
• 影响因子: 11.1
• 作者: Raven F;Ward JF;Zoltowska KM;Wan Y;Bylykbashi E;Miller SJ;Shen X;Choi SH;Rynearson KD;Berezovska O;Wagner SL;Tanzi RE;Zhang C
• 通讯作者: Zhang C