{"doi":"10.1177/2472555220958387","title":"AlphaScreen Identifies MSUT2 Inhibitors for Tauopathy-Targeting Therapeutic Discovery","abstract":"Tauopathies are neurological disorders characterized by intracellular tau deposits forming neurofibrillary tangles, neuropil threads, or other disease-specific aggregates composed of the protein tau. Tauopathy disorders include frontotemporal lobar degeneration, corticobasal degeneration, Pick's disease, and the largest cause of dementia, Alzheimer's disease. The lack of disease-modifying therapeutic strategies to address tauopathies remains a critical unmet need in dementia care. Thus, novel broad-spectrum tau-targeted therapeutics could have a profound impact in multiple tauopathy disorders, including Alzheimer's disease. Here we have designed a drug discovery paradigm to identify inhibitors of the pathological tau-enabling protein, MSUT2. We previously showed that activity of the RNA-binding protein MSUT2 drives tauopathy, including tau-mediated neurodegeneration and cognitive dysfunction, in mouse models. Thus, we hypothesized that MSUT2 inhibitors could be therapeutic for tauopathy disorders. Our pipeline for MSUT2 inhibitory compound identification included a primary AlphaScreen, followed by dose-response validation, a secondary fluorescence polarization orthogonal assay, a tertiary specificity screen, and a preliminary toxicity screen. Our work here serves as a proof-of-principle methodology for finding specific inhibitors of the poly(A) RNA-binding protein MSUT2 interaction. Here we identify 4,4'-diisothiocyanostilbene-2,2'-sulfonic acid (DIDS) as a potential tool compound for future work probing the mechanism of MSUT2-induced tau pathology.","journal":"SLAS DISCOVERY","year":2020,"id":111930,"datarank":0.30436569139010594,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.06295000452499085,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.06295000452499085,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":3,"citers_with_citation_signal":2,"citers_with_endowment":2,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.95,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":531155,"name":"Rikki L. Uhrich","orcid":null,"position":1,"is_corresponding":false},{"id":363968,"name":"Timothy J. Strovas","orcid":"0000-0002-0176-0293","position":2,"is_corresponding":false},{"id":351411,"name":"Aleen D. Saxton","orcid":"0000-0002-5055-5755","position":3,"is_corresponding":false},{"id":351412,"name":"Brian C. Kraemer","orcid":"0000-0002-2252-7634","position":4,"is_corresponding":false},{"id":472182,"name":"Jeremy D. Baker","orcid":null,"position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:13:09.353152Z","pmid":"32981422","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":[]}