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Discovery and Optimization of Tau Targeted Protein Degraders Enabled by Patient Induced Pluripotent Stem Cells-Derived Neuronal Models of Tauopathy

Accumulation of misfolded, aggregating proteins concurrent with disease onset and progression is a hallmark of neurodegenerative proteinopathies. An important class of these are tauopathies, such as frontotemporal dementia (FTD) and Alzheimer’s disease (AD), associated with accumulation of aberrant...

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Autores principales: Silva, M. Catarina, Nandi, Ghata, Donovan, Katherine A., Cai, Quan, Berry, Bethany C., Nowak, Radoslaw P., Fischer, Eric S., Gray, Nathanael S., Ferguson, Fleur M., Haggarty, Stephen J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8934437/
https://www.ncbi.nlm.nih.gov/pubmed/35317195
http://dx.doi.org/10.3389/fncel.2022.801179
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author Silva, M. Catarina
Nandi, Ghata
Donovan, Katherine A.
Cai, Quan
Berry, Bethany C.
Nowak, Radoslaw P.
Fischer, Eric S.
Gray, Nathanael S.
Ferguson, Fleur M.
Haggarty, Stephen J.
author_facet Silva, M. Catarina
Nandi, Ghata
Donovan, Katherine A.
Cai, Quan
Berry, Bethany C.
Nowak, Radoslaw P.
Fischer, Eric S.
Gray, Nathanael S.
Ferguson, Fleur M.
Haggarty, Stephen J.
author_sort Silva, M. Catarina
collection PubMed
description Accumulation of misfolded, aggregating proteins concurrent with disease onset and progression is a hallmark of neurodegenerative proteinopathies. An important class of these are tauopathies, such as frontotemporal dementia (FTD) and Alzheimer’s disease (AD), associated with accumulation of aberrant forms of tau protein in the brain. Pathological tau undergoes abnormal post-translational modifications, misfolding, oligomerization and changes in solubility, cellular redistribution, and spreading. Development and testing of experimental therapeutics that target these pathological tau conformers requires use of cellular models that recapitulate neuronal endogenous, non-heterologous tau expression under genomic and physiological contexts relevant to disease. In this study, we employed FTD-patient induced pluripotent stem cells (iPSC)-derived neurons, expressing a tau variant or mutation, as primary models for driving a medicinal chemistry campaign around tau targeting degrader series. Our screening goal was to establish structure-activity relationships (SAR) for the different chemical series to identify the molecular composition that most efficiently led to tau degradation in human FTD ex vivo neurons. We describe the identification of the lead compound QC-01-175 and follow-up optimization strategies for this molecule. We present three final lead molecules with tau degradation activity in mutant neurons, which establishes potential disease relevance and will drive future studies on specificity and pharmacological properties.
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spelling pubmed-89344372022-03-21 Discovery and Optimization of Tau Targeted Protein Degraders Enabled by Patient Induced Pluripotent Stem Cells-Derived Neuronal Models of Tauopathy Silva, M. Catarina Nandi, Ghata Donovan, Katherine A. Cai, Quan Berry, Bethany C. Nowak, Radoslaw P. Fischer, Eric S. Gray, Nathanael S. Ferguson, Fleur M. Haggarty, Stephen J. Front Cell Neurosci Neuroscience Accumulation of misfolded, aggregating proteins concurrent with disease onset and progression is a hallmark of neurodegenerative proteinopathies. An important class of these are tauopathies, such as frontotemporal dementia (FTD) and Alzheimer’s disease (AD), associated with accumulation of aberrant forms of tau protein in the brain. Pathological tau undergoes abnormal post-translational modifications, misfolding, oligomerization and changes in solubility, cellular redistribution, and spreading. Development and testing of experimental therapeutics that target these pathological tau conformers requires use of cellular models that recapitulate neuronal endogenous, non-heterologous tau expression under genomic and physiological contexts relevant to disease. In this study, we employed FTD-patient induced pluripotent stem cells (iPSC)-derived neurons, expressing a tau variant or mutation, as primary models for driving a medicinal chemistry campaign around tau targeting degrader series. Our screening goal was to establish structure-activity relationships (SAR) for the different chemical series to identify the molecular composition that most efficiently led to tau degradation in human FTD ex vivo neurons. We describe the identification of the lead compound QC-01-175 and follow-up optimization strategies for this molecule. We present three final lead molecules with tau degradation activity in mutant neurons, which establishes potential disease relevance and will drive future studies on specificity and pharmacological properties. Frontiers Media S.A. 2022-03-03 /pmc/articles/PMC8934437/ /pubmed/35317195 http://dx.doi.org/10.3389/fncel.2022.801179 Text en Copyright © 2022 Silva, Nandi, Donovan, Cai, Berry, Nowak, Fischer, Gray, Ferguson and Haggarty. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Silva, M. Catarina
Nandi, Ghata
Donovan, Katherine A.
Cai, Quan
Berry, Bethany C.
Nowak, Radoslaw P.
Fischer, Eric S.
Gray, Nathanael S.
Ferguson, Fleur M.
Haggarty, Stephen J.
Discovery and Optimization of Tau Targeted Protein Degraders Enabled by Patient Induced Pluripotent Stem Cells-Derived Neuronal Models of Tauopathy
title Discovery and Optimization of Tau Targeted Protein Degraders Enabled by Patient Induced Pluripotent Stem Cells-Derived Neuronal Models of Tauopathy
title_full Discovery and Optimization of Tau Targeted Protein Degraders Enabled by Patient Induced Pluripotent Stem Cells-Derived Neuronal Models of Tauopathy
title_fullStr Discovery and Optimization of Tau Targeted Protein Degraders Enabled by Patient Induced Pluripotent Stem Cells-Derived Neuronal Models of Tauopathy
title_full_unstemmed Discovery and Optimization of Tau Targeted Protein Degraders Enabled by Patient Induced Pluripotent Stem Cells-Derived Neuronal Models of Tauopathy
title_short Discovery and Optimization of Tau Targeted Protein Degraders Enabled by Patient Induced Pluripotent Stem Cells-Derived Neuronal Models of Tauopathy
title_sort discovery and optimization of tau targeted protein degraders enabled by patient induced pluripotent stem cells-derived neuronal models of tauopathy
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8934437/
https://www.ncbi.nlm.nih.gov/pubmed/35317195
http://dx.doi.org/10.3389/fncel.2022.801179
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