{"doi":"10.1101/2025.10.13.682036","title":"Ampyrone (4-Aminoantipyrine) is a Direct Agonist of Human Tyrosinase and Potential Therapeutic for Oculocutaneous Albinism and Disorders of Hypopigmentation","abstract":"Abstract Significant loss of pigmentation can increase visual disability, skin cancer risk, and psychosocial stress. Tyrosinase (TYR) catalyzes the first and rate-limiting step of melanin synthesis. Inhibitors of TYR are well established and are currently used in clinical settings; however, there is a dearth of direct activators of TYR. Here, using a unique human TYR construct, high-throughput screening, and computational analysis techniques, we identified ampyrone as a TYR activator. Ampyrone increased the in vitro catalytic activity of the intramelanosomal domain of human TYR (hTYR) and its hypomorphic variant, P406L, a cause of oculocutaneous albinism type 1B (OCA1B). Moreover, ampyrone induced melanin synthesis in both wild-type and OCA1B human melanocytes, as well as 3-dimension (3D) human skin cultures. Our results reveal ampyrone as a lead compound for first-in-class TYR activators, potentially accelerating the discovery of novel therapies for patients with genetic and acquired diseases of hypopigmentation.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":559308,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9558,"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":940237,"name":"Yuhong Wang","orcid":"0000-0001-6480-9528","position":1,"is_corresponding":false},{"id":740050,"name":"Nathan P. 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Boxer","orcid":null,"position":10,"is_corresponding":false},{"id":259681,"name":"Qiuying Chen","orcid":"0000-0001-5909-3959","position":11,"is_corresponding":false},{"id":259684,"name":"Steven S. Gross","orcid":"0000-0001-8029-2338","position":12,"is_corresponding":false},{"id":232217,"name":"Nabeel Attarwala","orcid":"0000-0003-2112-9754","position":13,"is_corresponding":false},{"id":251056,"name":"Yingyos Jittayasothorn","orcid":"0000-0001-6977-2728","position":14,"is_corresponding":false},{"id":793444,"name":"Ramakrishna P. Alur","orcid":null,"position":15,"is_corresponding":false},{"id":1461126,"name":"Diksha Shukla","orcid":null,"position":16,"is_corresponding":false},{"id":1461127,"name":"Robin Kee","orcid":null,"position":17,"is_corresponding":false},{"id":962471,"name":"Charles DeYoung","orcid":"0000-0002-8412-2173","position":18,"is_corresponding":false},{"id":428957,"name":"Cuilee Sha","orcid":"0000-0003-0188-2802","position":19,"is_corresponding":false},{"id":362136,"name":"David R. Adams","orcid":"0000-0002-6660-1242","position":20,"is_corresponding":false},{"id":758566,"name":"Stacie K. Loftus","orcid":"0000-0002-1958-4689","position":21,"is_corresponding":false},{"id":327342,"name":"Tiziana Cogliati","orcid":null,"position":22,"is_corresponding":false},{"id":99002,"name":"Yuri V. Sergeev","orcid":"0000-0002-7204-6572","position":23,"is_corresponding":false},{"id":281690,"name":"Jonathan H. 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