{"doi":"10.1073/pnas.2510496122","title":"Small-molecule allosteric activator of ubiquitin-specific protease 7 (USP7)","abstract":"Ubiquitin-specific protease 7 (USP7) is a deubiquitylase essential for cell homeostasis, DNA repair, and regulation of both tumor suppressors and oncogenes. Recently, haploinsufficiency of USP7 has been associated with Hao-Fountain syndrome (HAFOUS), a rare neurodevelopmental disorder. Although a range of USP7 inhibitors have been developed over the last decade, in the context of HAFOUS, USP7 activators may represent a more relevant approach. To address this challenge, we report the identification and characterization of a small-molecule activator of USP7 called MS-8. Structural and functional studies show that MS-8 allosterically activates USP7, mimicking the endogenous autoactivation mechanism of the enzyme. We observed that MS-8 engages and activates mutant USP7 in a cellular context, impacting downstream proteins. Taken together, our study provides validation of the USP7 activator that paves the way toward activation-driven USP7 pharmacology.","journal":"Proceedings of the National Academy of Sciences","year":2025,"id":527179,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9553,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":421265,"name":"Mona Sharafi","orcid":null,"position":1,"is_corresponding":false},{"id":1403845,"name":"Emilie J. Korchak","orcid":"0000-0002-6091-8636","position":2,"is_corresponding":false},{"id":958991,"name":"Andres Salazar‐Chaparro","orcid":null,"position":3,"is_corresponding":false},{"id":731618,"name":"Ariana S. Bratt","orcid":"0000-0001-6991-3906","position":4,"is_corresponding":false},{"id":1404510,"name":"Tvesha Parikh","orcid":null,"position":5,"is_corresponding":false},{"id":463162,"name":"Anthony C. Varca","orcid":"0000-0002-6308-2491","position":6,"is_corresponding":false},{"id":1189747,"name":"Binita Shah","orcid":"0000-0002-6084-3355","position":7,"is_corresponding":false},{"id":1404511,"name":"Michael G. Darnowski","orcid":null,"position":8,"is_corresponding":false},{"id":1153097,"name":"Mia Chung","orcid":"0009-0008-5631-1410","position":9,"is_corresponding":false},{"id":971974,"name":"Wei Pin Teh","orcid":"0000-0003-1090-7477","position":10,"is_corresponding":false},{"id":243062,"name":"Jianwei Che","orcid":"0000-0003-4956-4811","position":11,"is_corresponding":false},{"id":274272,"name":"Irina Bezsonova","orcid":"0000-0002-8629-0349","position":12,"is_corresponding":false},{"id":258075,"name":"Sara J. Buhrlage","orcid":"0000-0003-4562-1823","position":13,"is_corresponding":false},{"id":967725,"name":"Isabella Jaen Maisonet","orcid":"0000-0003-4996-3492","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-19T02:50:39.280101Z","pmid":"41086218","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":[]}