Targeted Dephosphorylation of Tau by Phosphorylation Targeting Chimeras (PhosTACs) as a Therapeutic Modality
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Microtubule-associated protein tau is essential for microtubule assembly and stabilization. Hyperphosphorylation of the microtubule-associated protein tau plays an important pathological role in the development of Alzheimer’s disease and other tauopathies. In vivo studies using kinase inhibitors suggest that reducing tau phosphorylation levels has therapeutic potential; however, such approaches showed limited benefits. We sought to further develop our phosphorylation targeting chimera (PhosTAC) technology to specifically induce tau dephosphorylation. Herein, we use small molecule-based PhosTACs to recruit tau to PP2A, a native tau phosphatase. PhosTACs induced the formation of a stable ternary complex, leading to rapid, efficient, and sustained tau dephosphorylation, which also correlated with the enhanced downregulation of tau protein. Mass spectrometry data validated that PhosTACs downregulated multiple phosphorylation sites of tau. We believe that PhosTAC possesses several advantages over current strategies to modulate tau phosphorylation and represents a new avenue for disease-modifying therapies for tauopathies.
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Crews laboratory developed PhosTACs after PROTAC.
“Crews laboratory developed another novel regulatory tool after PROTAC, namely Phosphorylation Targeting Chimeras (PhosTACs).”
From Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review (2024) · cites this paper as [206]
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- Authors
- Hu, Z., Chen, P.-H., Li, W., Douglas, T., Hines, J., Liu, Y., & Crews, C. M.
- Affiliations
- Yale University (US)
- Yale Cancer Center (US)
- Corresponding author
- Crews, Craig M.
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2023-02-08
- Volume
- 145
- Issue
- 7
- Pages
- 4045-4055
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- PMC
- PMC11670127
- OpenAlex
- W4319458885
- Cited by
- 98
- References
- 59
- Citations by year
- 2026: 31 · 2025: 23 · 2024: 32 · 2023: 12
- FWCI
- 17.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Journal of the American Chemical Society (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R35 CA197589)
- American Cancer Society
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- tau phosphorylation, tau dephosphorylation, protein phosphatase 2A, tauopathy, Alzheimer's disease, ternary complex formation, disease-modifying therapy
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