PTPRD phosphatase inhibitors for stimulant use disorders

PTPRD 磷酸酶抑制剂治疗兴奋剂使用障碍

• 批准号: 10710969
• 负责人: George Richard Uhl
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10710969
• 关键词: 3xTg-AD mouse; Aging; Alzheimer' s Disease; Apolipoprotein E; Behavioral; Biodistribution; Brain; Dementia; Development; Dietary intake; Flavones; Flavonols; Functional disorder; Genes; Genetic; Glycogen Synthase Kinases; Histologic; In Vitro; Lead; Modeling; Modification; Mus; Natural Products; Neurofibrillary Tangles; Pathogenicity; Pathologic; Pathology; Pharmaceutical Preparations; Phosphopeptides; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiological; Positioning Attribute; Property; Protein Dephosphorylation; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; Role; Specificity; Structure; Structure-Activity Relationship; Testing; Toxic effect; Translations; Tyrosine; Variant; Work; analog; drug candidate; drug market; glycogen synthase kinase 3 beta; hyperphosphorylated tau; improved; in silico; in vivo; neuropathology; novel; novel strategies; novel therapeutics; off-target site; phosphatase inhibitor; positive allosteric modulator; prevent; receptor; stimulant use disorder; tau Proteins; therapy development

Project Summary/Abstract Alzheimer’s disease (AD) receives pathogenic contributions from genetics [1, 2] and from environmental influences that include dietary intake of flavonols > flavones [4-8]. Neurofibrillary tangles (NFTs) rich in hyper- phosphorylated tau protein [10] are prominent features of AD neuropathology. NFT densities correlate well with the degree of AD dementia [15] [18] and are influenced by variation in the ApoE and PTPRD genes [3]. One approach to altering tau/NFT pathophysiology is to reduce activities of the kinases that hyper- phosphorylate tau. The glycogen synthase kinases GSK3α and GSK3β are prominent tau phosphorylators [19]. GSK3α and GSK3β are activated by phosphorylation of their own tyrosines (pY279 and pY216) by known tyrosine kinases [20] [21, 22]. Increasing activity of tyrosine phosphatase(s) that dephosphorylate and reduce activities of brain GSK3α and GSK3β thus provides a novel approach to reducing tau pathology in AD. Evidence (much developed during our prior NIA supplement support) now supports roles for: a) the receptor type protein tyrosine phosphatase PTPRD as both a key physiological phosphatase for phospho (pY) GSK3α and GSK3β and a novel target for decreasing pathological AD tau hyperphosphorylation, b) flavonols as lead compound PTPRD positive allosteric modulators (PAMs) that increase this desired PTPRD activity and c) structure activity relationships for natural product and novel flavonol analogs that supports the likelihood that further modifications will provide novel drug candidates. We will enhance this evidence and move toward translation by testing hypotheses that a) 8- position-substituted and other flavonol analogs will display enhanced positive allosteric modulation of PTPRD dephosphorylation of GSK3β/GSK3α b) this enhancement will display specificity with respect to activities at related phosphatases c) optimal analogs will display improved drug-like properties in silico and in vivo. Each of these attributes will allow us to develop and select improved, specific PTPRD PAMs that can reduce progression to AD deficits during aging. We will test these hypothesis and support development and translation of PTPRD PAMs in several ways: 1) We will synthesize and test novel flavonol analogs as improved PTPRD PAMs, testing these structures in vitro, refining our in silico models and nominating/synthesizing/testing new structures on the basis of these results, testing specificities vs other PTPRD substrate phosphopeptides and off-target sites of action of currently marketed drugs. We will test the most promising PTPRD PAMs in vivo for gross, histological or behavioral toxicities, biodistribution (including brain) and evidence for target engagement. We will begin testing of the best candidates in aging 3xTg-AD mice with or without reduced PTPRD expression. This work will advance our understanding of AD pathophysiology, validate novel approaches to PTPRD positive allosteric modulation and provide a basis for development of interventions that can prevent and/or treat key aspects of AD.

项目总结/摘要 阿尔茨海默病（AD）的致病因素来自遗传[1，2]和环境因素。 影响，包括膳食摄入黄酮醇>黄酮[4-8]。神经纤维缠结（NFT）富含超- 磷酸化tau蛋白[10]是AD神经病理学的突出特征。NFT密度与 AD痴呆的程度[15] [18]，并受ApoE和PTPRD基因变异的影响[3]。 改变tau/NFT病理生理学的一种方法是降低过度激活tau/NFT的激酶的活性。 磷酸化tau。糖原合成酶激酶GSK 3 α和GSK 3 β是主要的tau蛋白磷酸化酶 [19]第10段。GSK 3 α和GSK 3 β通过已知的酪氨酸磷酸化（pY 279和pY 216）被激活。 酪氨酸激酶[20] [21，22]。增加酪氨酸磷酸酶的活性，使其去磷酸化和还原 因此，脑GSK 3 α和GSK 3 β的活性提供了减少AD中tau病理的新方法。 证据（在我们之前的NIA补充支持期间得到了很大发展）现在支持以下方面的作用：a）受体 型蛋白酪氨酸磷酸酶PTPRD是磷酸化（pY）GSK 3 α的关键生理磷酸酶， 和GSK 3 β以及降低病理性AD tau过度磷酸化的新靶点，B）黄酮醇作为先导 化合物PTPRD正变构调节剂（PAM），其增加该期望的PTPRD活性，和c） 天然产物和新型黄酮醇类似物的构效关系支持了 进一步的修饰将提供新的候选药物。我们将加强这一证据， a）8位取代的和其他黄酮醇类似物将显示 增强了GSK 3 β/GSK 3 α的PTPRD去磷酸化的正向变构调节B）这种增强 c）最佳的类似物将显示出改善的 在计算机和体内的药物样性质。这些属性中的每一个都将使我们能够开发和选择改进的， 特异性PTPRD PAM，可以减少衰老过程中AD缺陷的进展。 我们将测试这些假设，并以几种方式支持PTPRD PAM的开发和翻译： 我们将合成和测试新的黄酮醇类似物作为改进的PTPRD PAM，在体外测试这些结构， 改进我们的计算机模型并根据这些结果提名/合成/测试新结构， 测试与其他PTPRD底物磷酸肽和目前的脱靶作用位点相比的特异性 市售药品。我们将在体内测试最有前途的PTPRD PAM的大体、组织学或行为学 毒性、生物分布（包括大脑）和目标参与的证据。我们将开始测试最好的 在具有或不具有降低的PTPRD表达的衰老3xTg-AD小鼠中的候选物。这项工作将促进我们的 了解AD病理生理学，验证PTPRD正变构调节的新方法， 为开发可以预防和/或治疗AD关键方面的干预措施提供基础。