Structure-based Identification and Functional Characterization of SSH1 Inhibitors
Structure-based Identification and Functional Characterization of SSH1 Inhibitors
批准号:
8872959
负责人:
Yu Chen
金额:
$22.43万
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
已结题
起止时间:
2015-09-01 至 2017-03-31
关键词:
APP-PS1ActinsAlzheimer&aposs DiseaseAmyloidAmyloid beta-ProteinApoptosisBiologicalBiological AssayBrainCatalytic DomainCellsCharacteristicsChemicalsComplexCysteineDockingDrug KineticsExhibitsF-ActinFeedbackFutureImpaired cognitionImpairmentIn VitroInduction of ApoptosisLIMK1 geneLeadLigand BindingLigandsLinkMitochondriaModelingModificationMolecularMusOxidative StressPathologyPathway interactionsPatientsPhosphoric Monoester HydrolasesPhosphorylationProductionProtein DephosphorylationProteinsRoentgen RaysScaffolding ProteinSignal TransductionSite-Directed MutagenesisSpecificityStructural ModelsStructureStructure-Activity RelationshipSuperoxidesSurfaceSynapsesTherapeuticabeta accumulationbasecofilincofilin 2designfunctional groupimprovedinhibitor/antagonistmitochondrial dysfunctionneurotoxicneurotoxicitynovelpreventpublic health relevanceresearch studyretinal rodsscreeningtau Proteinstau dysfunctiontherapeutic targetvirtual
中文摘要
英文摘要
DESCRIPTION (provided by applicant): As the major defining characteristic of Alzheimer's disease (AD) brains is the excessive accumulation of toxic proteins called Aβ and Tau, understanding the biological mechanisms by which Aβ connects to tau dysfunction are critical for designing effective therapeutic treatments for AD. We have identified SSH1, a phosphatase that activates Cofilin, as a promising therapeutic target for AD, as SSH1 impacts both Aβ and Tau. We have also identified several SSH1 inhibitor compounds that effectively decrease both Aβ-induced neurotoxicity and Tau hyperphosphorylation while decreasing Aβ production. In the proposal, we will perform chemical modifications of SSH1 inhibitor compounds to verify the functional groups critical for SSH1 inhibition and establish a platform for lead optimization. We will optimize and carry out in vitro phosphatase activity assays for SSH1 and other dual specificity phosphatases. We will also perform AD-relevant cell-based assays using existing and chemically modified compounds. Complex X-ray crystal structures will be determined using existing and modified compounds in physical contact with the catalytic domain of SSH1, to investigate the molecular basis of their interactions. Double perturbation experiments will be used to probe the contribution of specific inhibitor functional groups and protein residues to ligand binding using modified compounds and site-specific mutagenesis of SSH1. Based on a revised structural model, virtual docking and structure-based design will be performed to improve existing ligand efficiency, and new virtual screening will be carried out to identify additional SSH1 inhibitor chemotypes. Finally, based on the new structure-based ligand efficiency model, we will perform synthesis of a modified compound to demonstrate the proof-of-concept that such modified compound exhibits improved SSH1 inhibitory activity and ADME characteristics in vitro. Therefore, results of this R21 proposal are expected to yield valuable structure function relationship between SSH1 and existing and new compounds as well as establish a structure-based platform for extensive lead optimization and pharmacokinetic studies in a future R01 proposal.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Defining the role of histone H3K4 mono-methyltransferase dysfunction in urothelial carcinoma
-
批准号:10522552
-
项目类别:
-
资助金额:$60.23万
-
财政年份:2022
-
负责人:Yu Chen
-
依托单位:
Automatic Wide-Field Optical Coherence Tomography for Assessment of Transplant Kidney Viability
-
批准号:10501992
-
项目类别:
-
资助金额:$67.19万
-
财政年份:2022
-
负责人:Yu Chen
-
依托单位:
Iodine Catalyzed Cross-Coupling Reactions
-
批准号:10333396
-
项目类别:
-
资助金额:$10.36万
-
财政年份:2022
-
负责人:Yu Chen
-
依托单位:
Iodine Catalyzed Cross-Coupling Reactions
-
批准号:10643819
-
项目类别:
-
资助金额:$11.55万
-
财政年份:2022
-
负责人:Yu Chen
-
依托单位:
Evolution and inhibition of carbapenemase in beta-lactam resistance
-
批准号:10598501
-
项目类别:
-
资助金额:$73.04万
-
财政年份:2021
-
负责人:Yu Chen
-
依托单位:
Evolution and inhibition of carbapenemase in beta-lactam resistance
-
批准号:10385772
-
项目类别:
-
资助金额:$73.85万
-
财政年份:2021
-
负责人:Yu Chen
-
依托单位:
Patient-Derived Models of Prostate Cancer for Personalized Medicine
-
批准号:10472536
-
项目类别:
-
资助金额:$100.55万
-
财政年份:2019
-
负责人:Yu Chen
-
依托单位:
Patient-Derived Models of Prostate Cancer for Personalized Medicine
-
批准号:10219178
-
项目类别:
-
资助金额:$102.6万
-
财政年份:2019
-
负责人:Yu Chen
-
依托单位:
Patient-Derived Models of Prostate Cancer for Personalized Medicine
-
批准号:10683753
-
项目类别:
-
资助金额:$100.55万
-
财政年份:2019
-
负责人:Yu Chen
-
依托单位:
Understanding the role of an aberrant hepatic nuclear transcription circuit in prostate cancer tumorigenesis and castration resistance
-
批准号:10224110
-
项目类别:
-
资助金额:$49.96万
-
财政年份:2017
-
负责人:Yu Chen
-
依托单位:
Understanding the role of an aberrant hepatic nuclear transcription circuit in prostate cancer tumorigenesis and castration resistance
-
批准号:9753189
-
项目类别:
-
资助金额:$48.17万
-
财政年份:2017
-
负责人:Yu Chen
-
依托单位:
Project 2: Reversing resistance caused by lineage plasticity through epigenetic therapy
-
批准号:10250362
-
项目类别:
-
资助金额:$47.55万
-
财政年份:2017
-
负责人:Yu Chen
-
依托单位:
Project 2: Reversing resistance caused by lineage plasticity through epigenetic therapy
-
批准号:9446577
-
项目类别:
-
资助金额:$43.33万
-
财政年份:2017
-
负责人:Yu Chen
-
依托单位:
Project 2: Reversing resistance caused by lineage plasticity through epigenetic therapy
-
批准号:10005211
-
项目类别:
-
资助金额:$51.04万
-
财政年份:2017
-
负责人:Yu Chen
-
依托单位:
Understanding the role of an aberrant hepatic nuclear transcription circuit in prostate cancer tumorigenesis and castration resistance
-
批准号:9384475
-
项目类别:
-
资助金额:$49.86万
-
财政年份:2017
-
负责人:Yu Chen
-
依托单位:
Foregut Microbiome and Risk of Gastric Intestinal Metaplasia, and Gastric Cancer Risk
-
批准号:9080967
-
项目类别:
-
资助金额:$87.73万
-
财政年份:2016
-
负责人:Yu Chen
-
依托单位:
Foregut Microbiome and Risk of Gastric Intestinal Metaplasia, and Gastric Cancer Risk
-
批准号:9899944
-
项目类别:
-
资助金额:$66.58万
-
财政年份:2016
-
负责人:Yu Chen
-
依托单位:
The NYU Women's Health Study
-
批准号:10165582
-
项目类别:
-
资助金额:$54.61万
-
财政年份:2015
-
负责人:Yu Chen
-
依托单位:
Three-Dimensional Image-Guided Development and Optimization of Molecular Regulating Bone Regenerative Scaffolds
-
批准号:8887845
-
项目类别:
-
资助金额:$32.07万
-
财政年份:2015
-
负责人:Yu Chen
-
依托单位:
Three-Dimensional Image-Guided Development and Optimization of Molecular Regulating Bone Regenerative Scaffolds
-
批准号:9063060
-
项目类别:
-
资助金额:$32.28万
-
财政年份:2015
-
负责人:Yu Chen
-
依托单位:
海外基金