High Throughput screen to identify "first of their kind" activators of ADCY10

高通量筛选，鉴定 ADCY10 的“同类首个”激活剂

• 批准号: 10318579
• 负责人: JOCHEN BUCK
• 金额: $ 56.94万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2023-09-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318579
• 关键词: Adenylate Cyclase; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Anions; Autophagocytosis; Autophagolysosome; Bicarbonates; Biochemical; Biological; Biological Assay; Biological Models; Brain Diseases; Carbon Dioxide; Cathepsins; Cell Nucleus; Cell membrane; Cell model; Cell physiology; Cells; Clinical Trials; Complement; Complex; Cyclic AMP; Data; Defect; Dementia; Disease; Environment; Epidemic; Equilibrium; Exhibits; Family; Genetic; Heterotrimeric GTP-Binding Proteins; Hormones; Human; In Vitro; Knock-out; Laboratories; Lipids; Liquid substance; Lumen of the Lysosome; Lysosomes; Mammalian Cell; Methodology; Microglia; Mitochondrial Matrix; Mitotic; Modeling; Molecular; Mus; Nature; Neurodegenerative Disorders; Neurons; Organelles; Orthologous Gene; Palliative Care; Parkinson Disease; Pathologic; Pathology; Pathway interactions; Patients; Permeability; Pharmacology; Phase; Physiological; Polysaccharides; Process; Proteins; Regulation; Research; Second Messenger Systems; Services; Signal Transduction; Source; Symptoms; System; Testing; Therapeutic; age related neurodegeneration; aged; alkalinity; base; carbonate dehydratase; disease-causing mutation; high throughput screening; improved; inhibitor; misfolded protein; novel strategies; presenilin-1; protein aggregation; protein degradation; sensor; small molecule; therapeutically effective; tool; treatment strategy

Aberrant accumulation of protein aggregates is a common feature of age-related neurodegenerative diseases, including Alzheimer's disease. Cells clear aggregated material via autophagy. Lysosomes, the acidic organelles where proteins and unused cellular components are degraded and recycled, are the terminal compartment of autophagy. Long-lived, post-mitotic cells such as neurons are dependent upon continuous lysosomal turnover of cellular materials delivered by autophagy. With aging, lysosomes become less acidic, and their proteolytic activity decreases. In a cellular model of Alzheimer's disease, re-acidification of lysosomal pH increases autophagic flux and rescues cell function. We discovered a signaling cascade which regulates lysosomal acidification. Soluble adenylyl cyclase (sAC) is a source of the ubiquitous second messenger cAMP which is molecularly, structurally, biochemically, and functionally distinct from the family of plasma membrane-bound, hormone-regulated transmembrane forms of adenylyl cyclase. We showed sAC-generated cAMP promotes lysosomal acidification, and in the absence of sAC activity, autophagic flux is slowed. There are no pharmacological activators of sAC. We previously used high throughput screening to identify the most widely used pharmacological inhibitors specific sAC. We now propose to use high throughput screening and our battery of in vitro and cellular sAC assays to identify and characterize “first-of-their kind” small molecule activators selective for sAC usable in cellular systems. We hypothesize that sAC activators will facilitate lysosomal acidification and increase degradation of accumulated protein aggregates in cellular models of neurodegenerative disorders. These studies have the potential to supply proof- of-principle for a therapeutic strategy to treat neurodegenerative disorders.

蛋白质聚集体的异常积累是与年龄相关的常见特征 神经退行性疾病，包括阿尔茨海默氏病。细胞通过 自噬。溶酶体，酸性细胞器，其中蛋白质和未使用的细胞成分 被降解并回收，是自噬的末端室。寿命长，有丝分裂 细胞（例如神经元）取决于细胞材料的连续溶酶体周转率 由自噬交付。随着衰老，溶酶体变得较少酸性，其蛋白水解活性 在阿尔茨海默氏病的细胞模型中，溶酶体pH的重新循环 自噬通量并挽救细胞功能。我们发现了一个调节的信号级联 溶酶体酸化。可溶性腺苷酸环化酶（SAC）是无处不在的秒数 Messenger营地在分子，结构，生化和功能上与 质膜结合的家族，由马匹调节的adnylyl的跨膜形式 循环酶。我们显示出囊囊的营地促进了溶酶体酸化，并且在不存在的情况下 在SAC活性中，自噬通量会减慢。没有SAC的药物激活剂。我们 以前使用的高吞吐量筛选以识别最广泛使用的药物 抑制剂特定的囊。我们现在建议使用高吞吐量筛选和我们的电池 体外和细胞囊测定，以识别和表征“首先类型”的小分子 激活剂可在细胞系统中选择SAC。我们假设SAC激活剂将 促进溶酶体酸化并增加累积蛋白质聚集体的降解 神经退行性疾病的细胞模型。这些研究有可能提供证明 - 用于治疗神经退行性疾病的治疗策略的原则。

项目成果

Assessing potency and binding kinetics of soluble adenylyl cyclase (sAC) inhibitors to maximize therapeutic potential.

• DOI: 10.3389/fphys.2022.1013845
• 发表时间: 2022
• 期刊: Frontiers in physiology
• 影响因子: 4

Strategies to safely target widely expressed soluble adenylyl cyclase for contraception.

• DOI: 10.3389/fphar.2022.953903
• 发表时间: 2022
• 期刊: FRONTIERS IN PHARMACOLOGY
• 影响因子: 5.6
• 作者: Ferreira, Jacob;Levin, Lonny R.;Buck, Jochen
• 通讯作者: Buck, Jochen

Design, Synthesis, and Pharmacological Evaluation of Second-Generation Soluble Adenylyl Cyclase (sAC, ADCY10) Inhibitors with Slow Dissociation Rates.

• DOI: 10.1021/acs.jmedchem.2c01133
• 发表时间: 2022-11-24
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Miller, Michael;Rossetti, Thomas;Ferreira, Jacob;Ghanem, Lubna;Balbach, Melanie;Kaur, Navpreet;Levin, Lonny R.;Buck, Jochen;Kehr, Maria;Coquille, Sandrine;Heuvel, Joop van den;Steegborn, Clemens;Fushimi, Makoto;Finkin-Groner, Efrat;Myers, Robert W.;Kargman, Stacia;Liverton, Nigel J.;Huggins, David J.;Meinke, Peter T.
• 通讯作者: Meinke, Peter T.