{"doi":"10.3390/ijms242015216","title":"Tolfenamic Acid Derivatives: A New Class of Transcriptional Modulators with Potential Therapeutic Applications for Alzheimer’s Disease and Related Disorders","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.","journal":"International Journal of Molecular Sciences","year":2023,"id":356406,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9518,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1105120,"name":"Karim E. Shalaby","orcid":"0000-0001-5619-9619","position":1,"is_corresponding":false},{"id":769516,"name":"Syed Waseem Bihaqi","orcid":"0000-0002-0394-7887","position":2,"is_corresponding":false},{"id":1105537,"name":"Bothaina H. Alansi","orcid":null,"position":3,"is_corresponding":false},{"id":317822,"name":"Benjamin Barlock","orcid":"0000-0001-9160-4122","position":4,"is_corresponding":false},{"id":409999,"name":"Keykavous Parang","orcid":"0000-0001-8600-0893","position":5,"is_corresponding":false},{"id":1105121,"name":"I. Richard Thompson","orcid":"0000-0002-9554-550X","position":6,"is_corresponding":false},{"id":1105122,"name":"Khalid Ouararhni","orcid":"0000-0002-1245-3758","position":7,"is_corresponding":false},{"id":1105538,"name":"Nasser H. Zawia","orcid":null,"position":8,"is_corresponding":false},{"id":833691,"name":"Jaunetta Hill","orcid":"0000-0002-1303-3632","position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":null,"created_at":"2026-07-19T01:13:25.429924Z","pmid":"37894896","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}