PTPRD phosphatase inhibitors for stimulant use disorders

点击翻译按钮获取中文摘要

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.