Tolfenamic Acid Derivatives: A New Class of Transcriptional Modulators with Potential Therapeutic Applications for Alzheimer’s Disease and Related Disorders

Authors

Juanetta Hill, University of Rhode Island
Karim E. Shalaby, Hamad Bin Khalifa University (HBKU)
Syed W. Bihaqi, University of Rhode Island
Bothaina H. Alansi, University of Rhode Island
Benjamin Barlock, University of Rhode Island
Keykavous Parang, Chapman UniversityFollow
Richard Thompson, Hamad Bin Khalifa University (HBKU)
Khalid Ourarhni, Hamad Bin Khalifa University (HBKU)
Nasser H. Zawia, University of Rhode Island

Document Type

Article

Publication Date

10-16-2023

Abstract

The field of Alzheimer’s disease (AD) has witnessed recent breakthroughs in the development of disease-modifying biologics and diagnostic markers. While immunotherapeutic interventions have provided much-awaited solutions, nucleic acid-based tools represent other avenues of intervention; however, these approaches are costly and invasive, and they have serious side effects. Previously, we have shown in AD animal models that tolfenamic acid (TA) can lower the expression of AD-related genes and their products and subsequently reduce pathological burden and improve cognition. Using TA as a scaffold and the zinc finger domain of SP1 as a pharmacophore, we developed safer and more potent brain-penetrating analogs that interfere with sequence-specific DNA binding at transcription start sites and predominantly modulate the expression of SP1 target genes. More importantly, the proteome of treated cells displayed ~75% of the downregulated products as SP1 targets. Specific levels of SP1-driven genes and AD biomarkers such as amyloid precursor protein (APP) and Tau proteins were also decreased as part of this targeted systemic response. These small molecules, therefore, offer a viable alternative to achieving desired therapeutic outcomes by interfering with both amyloid and Tau pathways with limited off-target systemic changes.

Comments

This article was originally published in International Journal of Molecular Sciences, volume 24, issue 20, in 2023. https://doi.org/10.3390/ijms242015216

Recommended Citation

Hill, J.; Shalaby, K.E.; Bihaqi, S.W.; Alansi, B.H.; Barlock, B.; Parang, K.; Thompson, R.; Ouararhni, K.; Zawia, N.H. Tolfenamic Acid Derivatives: A New Class of Transcriptional Modulators with Potential Therapeutic Applications for Alzheimer’s Disease and Related Disorders. Int. J. Mol. Sci. 2023, 24, 15216. https://doi.org/10.3390/ijms242015216

Copyright

The authors

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.