{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:48:42Z","timestamp":1787028522011,"version":"build-2736575974"},"reference-count":39,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T00:00:00Z","timestamp":1697414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"the National Institutes of Health","doi-asserted-by":"publisher","award":["R36AG062868"],"award-info":[{"award-number":["R36AG062868"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"the National Institutes of Health","doi-asserted-by":"publisher","award":["IGP5"],"award-info":[{"award-number":["IGP5"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Qatar Biomedical Research Institute\u2019s Internal","award":["R36AG062868"],"award-info":[{"award-number":["R36AG062868"]}]},{"name":"the Qatar Biomedical Research Institute\u2019s Internal","award":["IGP5"],"award-info":[{"award-number":["IGP5"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The field of Alzheimer\u2019s 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.<\/jats:p>","DOI":"10.3390\/ijms242015216","type":"journal-article","created":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T01:31:22Z","timestamp":1697419882000},"page":"15216","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Tolfenamic Acid Derivatives: A New Class of Transcriptional Modulators with Potential Therapeutic Applications for Alzheimer\u2019s Disease and Related Disorders"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1303-3632","authenticated-orcid":false,"given":"Jaunetta","family":"Hill","sequence":"first","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5619-9619","authenticated-orcid":false,"given":"Karim E.","family":"Shalaby","sequence":"additional","affiliation":[{"name":"Neurological Disorder Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha 34110, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed W.","family":"Bihaqi","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bothaina H.","family":"Alansi","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9160-4122","authenticated-orcid":false,"given":"Benjamin","family":"Barlock","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8600-0893","authenticated-orcid":false,"given":"Keykavous","family":"Parang","sequence":"additional","affiliation":[{"name":"Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9554-550X","authenticated-orcid":false,"given":"Richard","family":"Thompson","sequence":"additional","affiliation":[{"name":"Neurological Disorder Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha 34110, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1245-3758","authenticated-orcid":false,"given":"Khalid","family":"Ouararhni","sequence":"additional","affiliation":[{"name":"Neurological Disorder Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha 34110, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nasser H.","family":"Zawia","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA"},{"name":"Neurological Disorder Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha 34110, Qatar"},{"name":"George and Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, USA"},{"name":"Interdisciplinary Neuroscience Program, University of Rhode Island, Kingston, RI 02881, USA"},{"name":"Biological and Biomedical Sciences Division, College of Health & Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha 34110, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Hill, J., and Zawia, N.H. (2021). Fenamates as Potential Therapeutics for Neurodegenerative Disorders. Cells, 10.","DOI":"10.3390\/cells10030702"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"655","DOI":"10.2174\/1567205015666180119104036","article-title":"Tolfenamic Acid: A Modifier of the Tau Protein and its Role in Cognition and Tauopathy","volume":"15","author":"Chang","year":"2018","journal-title":"Curr. Alzheimer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1111\/jnc.12960","article-title":"Tolfenamic acid reduces tau and CDK5 levels: Implications for dementia and tauopathies","volume":"133","author":"Adwan","year":"2015","journal-title":"J. Neurochem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2421","DOI":"10.1016\/j.neurobiolaging.2013.04.002","article-title":"Short-term treatment with tolfenamic acid improves cognitive functions in Alzheimer\u2019s disease mice","volume":"34","author":"Subaiea","year":"2013","journal-title":"Neurobiol. Aging"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/0006-291X(89)92437-6","article-title":"Characterization of the 5\u2032-end region and the first two exons of the \u03b2-protein precursor gene","volume":"159","author":"Lahiri","year":"1989","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2807","DOI":"10.1002\/j.1460-2075.1988.tb03136.x","article-title":"The promoter of Alzheimer\u2019s disease amyloid A4 precursor gene","volume":"7","author":"Salbaum","year":"1988","journal-title":"EMBO J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1093\/nar\/20.1.63","article-title":"The expression of the amyloid precursor protein (APP) is regulated by two GC-elements in the promoter","volume":"20","author":"Pollwein","year":"1992","journal-title":"Nucleic Acids Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2229","DOI":"10.1093\/nar\/23.12.2229","article-title":"DNA binding and regulatory effects of transcription factors SP1 and USF at the rat amyloid precursor protein gene promoter","volume":"23","author":"Hoffman","year":"1995","journal-title":"Nucleic Acids Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1042\/BJ20040682","article-title":"Sp1 and Smad transcription factors co-operate to mediate TGF-\u03b2-dependent activation of amyloid-\u03b2 precursor protein gene transcription","volume":"383","author":"Docagne","year":"2004","journal-title":"Biochem. J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1523\/JNEUROSCI.4335-04.2005","article-title":"The Fetal Basis of Amyloidogenesis: Exposure to Lead and Latent Overexpression of Amyloid Precursor Protein and \u03b2-Amyloid in the Aging Brain","volume":"25","author":"Basha","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.neulet.2005.11.062","article-title":"Abnormal Sp1 transcription factor expression in Alzheimer disease and tauopathies","volume":"397","author":"Santpere","year":"2006","journal-title":"Neurosci. Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1046\/j.1471-4159.2000.0751408.x","article-title":"Tau Promoter Confers Neuronal Specificity and Binds Sp1 and AP-2","volume":"75","author":"Ginzburg","year":"2000","journal-title":"J. Neurochem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.3233\/JAD-201139","article-title":"Molecular Processing of Tau Protein in Progressive Supranuclear Palsy: Neuronal and Glial Degeneration","volume":"79","author":"Harrington","year":"2021","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Puangmalai, N., Bhatt, N., Montalbano, M., Sengupta, U., Gaikwad, S., Ventura, F., McAllen, S., Ellsworth, A., Garcia, S., and Kayed, R. (2020). Internalization mechanisms of brain-derived tau oligomers from patients with Alzheimer\u2019s disease, progressive supranuclear palsy and dementia with Lewy bodies. Cell Death Dis., 11.","DOI":"10.1038\/s41419-020-2503-3"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"860","DOI":"10.2174\/156720511798192691","article-title":"The ability of tolfenamic acid to penetrate the brain: A model for testing the brain disposition of candidate Alzheimer\u2019s drugs using multiple platforms","volume":"8","author":"Subaiea","year":"2011","journal-title":"Curr. Alzheimer Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Rodriguez, S., Hug, C., Todorov, P., Moret, N., Boswell, S.A., Evans, K., Zhou, G., Johnson, N.T., Hyman, B.T., and Sorger, P.K. (2021). Machine learning identifies candidates for drug repurposing in Alzheimer\u2019s disease. Nat. Commun., 12.","DOI":"10.1038\/s41467-021-21330-0"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1074\/mcp.R115.053330","article-title":"Neurodegeneration and Alzheimer\u2019s disease (AD). What Can Proteomics Tell Us About the Alzheimer\u2019s Brain?","volume":"15","author":"Perlson","year":"2016","journal-title":"Mol. Cell. Proteom."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"71","DOI":"10.3233\/JAD-2008-13108","article-title":"Co-localization and Distribution of Cerebral APP and SP1 and its Relationship to Amyloidogenesis","volume":"13","author":"Brock","year":"2008","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"16027","DOI":"10.1021\/bi048438p","article-title":"NMR structure of transcription factor Sp1 DNA binding domain","volume":"43","author":"Oka","year":"2004","journal-title":"Biochemistry"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1093\/bioinformatics\/btt703","article-title":"Causal analysis approaches in Ingenuity Pathway Analysis","volume":"30","author":"Green","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1093\/jnci\/djj232","article-title":"Tolfenamic Acid and Pancreatic Cancer Growth, Angiogenesis, and Sp Protein Degradation","volume":"98","author":"Abdelrahim","year":"2006","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_22","first-page":"513","article-title":"The Role of the Ubiquitously Expressed Transcription Factor Sp1 in Tissue-specific Transcriptional Regulation and in Disease","volume":"89","author":"Gilmour","year":"2016","journal-title":"Yale J. Biol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5929","DOI":"10.1242\/dev.00832","article-title":"The role of buttonhead and Sp1 in the development of the ventral imaginal discs of Drosophila","volume":"130","author":"Estella","year":"2003","journal-title":"Development"},{"key":"ref_24","first-page":"2189","article-title":"Developmental Expression of Sp1 in the Mouse","volume":"11","author":"Saffer","year":"1991","journal-title":"Mol. Cell. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1242\/dev.106054","article-title":"A crucial role for the ubiquitously expressed transcription factor Sp1 at early stages of hematopoietic specification","volume":"141","author":"Gilmour","year":"2014","journal-title":"Development"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1038\/sj.ejhg.5201459","article-title":"Genomics: The amazing complexity of the human transcriptome","volume":"13","author":"Frith","year":"2005","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Cummings, J., Lee, G., Nahed, P., Kambar, M.E.Z.N., Zhong, K., Fonseca, J., and Taghva, K. (2022). Alzheimer\u2019s disease drug development pipeline: 2022. Alzheimer\u2019s Dement. Transl. Res. Clin. Interv., 8.","DOI":"10.1002\/trc2.12295"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1038\/s41591-023-02326-3","article-title":"Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer\u2019s disease: A phase 1b, randomized, placebo-controlled trial","volume":"29","author":"Mummery","year":"2023","journal-title":"Nat. Med."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Wegmann, S., DeVos, S.L., Zeitler, B., Marlen, K., Bennett, R.E., Perez-Rando, M., MacKenzie, D., Yu, Q., Commins, C., and Bannon, R.N. (2021). Persistent repression of tau in the brain using engineered zinc finger protein transcription factors. Sci. Adv., 7.","DOI":"10.1126\/sciadv.abe1611"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/S0006-2952(98)00088-4","article-title":"Opioid analgesics as noncompetitive N-methyl-d-aspartate (NMDA) antagonists","volume":"56","author":"Ebert","year":"1998","journal-title":"Biochem. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Chartoff, E.H., and Connery, H.S. (2014). It\u2019s MORe exciting than mu: Crosstalk between mu opioid receptors and glutamatergic transmission in the mesolimbic dopamine system. Front. Pharmacol., 5.","DOI":"10.3389\/fphar.2014.00116"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1111\/j.1471-4159.2008.05335.x","article-title":"Regulation of dendritic spine morphology by an NMDA receptor-associated Rho GTPase-activating protein, p250GAP","volume":"105","author":"Nakazawa","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.2174\/1567205015666180801095925","article-title":"Influence of Early Life Lead (Pb) Exposure on \u03b1-Synuclein, GSK-3\u03b2 and Caspase-3 Mediated Tauopathy: Implications on Alzheimer\u2019s Disease","volume":"15","author":"Bihaqi","year":"2018","journal-title":"Curr. Alzheimer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4134","DOI":"10.1021\/acs.jproteome.7b00505","article-title":"Multiplex and Label-Free Relative Quantification Approach for Studying Protein Abundance of Drug Metabolizing Enzymes in Human Liver Microsomes Using SWATH-MS","volume":"16","author":"Jamwal","year":"2017","journal-title":"J. Proteome Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.gpb.2019.09.006","article-title":"hTFtarget: A Comprehensive Database for Regulations of Human Transcription Factors and Their Targets","volume":"18","author":"Zhang","year":"2020","journal-title":"Genom. Proteom. Bioinform."},{"key":"ref_36","unstructured":"R Core Team (2018). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing. Available online: https:\/\/www.r-project.org\/."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/nmeth.3252","article-title":"Orchestrating high-throughput genomic analysis with Bioconductor","volume":"12","author":"Huber","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Wickham, H. (2008). Elegant Graphics for Data Analysis: Ggplot2, Springer.","DOI":"10.1007\/978-0-387-98141-3"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Ritchie, M.E., Phipson, B., Wu, D., Hu, Y., Law, C.W., Shi, W., and Smyth, G.K. (2015). limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res., 43.","DOI":"10.1093\/nar\/gkv007"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/20\/15216\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:07:23Z","timestamp":1760130443000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/20\/15216"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,16]]},"references-count":39,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["ijms242015216"],"URL":"https:\/\/doi.org\/10.3390\/ijms242015216","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,16]]}}}