{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T17:51:08Z","timestamp":1775929868669,"version":"3.50.1"},"posted":{"date-parts":[[2025,2,20]]},"group-title":"Pharmacology and Toxicology","reference-count":84,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T00:00:00Z","timestamp":1740009600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,2,20]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Melanogenesis is the biological process regulating the synthesis of melanin pigments in melanocytes. Defective melanogenesis is associated with numerous human skin diseases, including, but not limited to, albinism, vitiligo, melasma, and hypo- and hyperpigmentation disorders. Tyrosinase is the rate-limiting enzyme controlling melanogenesis, and hence tremendous efforts have been made to identify potent and safe inhibitors of tyrosinase function. However, despite decades of research, currently there is no effective treatment that inhibits melanogenesis or tyrosinase activity with no adverse side effects. In this study, we report characterization of the ML233 chemical as a potent inhibitor of tyrosinase activity\n                  <jats:italic>in vivo<\/jats:italic>\n                  and\n                  <jats:italic>in vitro<\/jats:italic>\n                  . We demonstrate that ML233 reduces melanin production in the zebrafish model with no observable significant toxic side effects, and in murine melanoma cells. We also predict that these effects are mediated through direct tyrosinase-ML233 interaction, i.e., binding of the ML233 molecule to the active site of the protein to inhibit its function. Together, our results reveal that ML233 plays roles in both healthy and pathological skin cells via inhibition of melanin production. ML233-mediated tyrosinase inhibition is a potentially safe and effective approach to alleviate the symptoms of melanocyte-associated diseases and thereby substantially improve human health.\n                <\/jats:p>","DOI":"10.1101\/2025.02.16.638443","type":"posted-content","created":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T02:30:21Z","timestamp":1740105021000},"source":"Crossref","is-referenced-by-count":1,"title":["The small molecule ML233 is a direct inhibitor of tyrosinase function"],"prefix":"10.64898","author":[{"given":"Romain","family":"Menard","sequence":"first","affiliation":[{"name":"MDI Biological Laboratory, Kathryn W. Davis Center for Regenerative Biology and Aging, Bar Harbor, Maine, United States of America"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aissette","family":"Baanannou","sequence":"additional","affiliation":[{"name":"MDI Biological Laboratory, Kathryn W. Davis Center for Regenerative Biology and Aging, Bar Harbor, Maine, United States of America"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caroline","family":"Halluin","sequence":"additional","affiliation":[{"name":"MDI Biological Laboratory, Kathryn W. Davis Center for Regenerative Biology and Aging, Bar Harbor, Maine, United States of America"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dexter","family":"Morse","sequence":"additional","affiliation":[{"name":"MDI Biological Laboratory, Kathryn W. Davis Center for Regenerative Biology and Aging, Bar Harbor, Maine, United States of America"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sadie","family":"Kuhn","sequence":"additional","affiliation":[{"name":"MDI Bioscience, Bar Harbor, Maine, United States of America"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joel H.","family":"Graber","sequence":"additional","affiliation":[{"name":"MDI Biological Laboratory, Kathryn W. Davis Center for Regenerative Biology and Aging, Bar Harbor, Maine, United States of America"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James","family":"Strickland","sequence":"additional","affiliation":[{"name":"MDI Bioscience, Bar Harbor, Maine, United States of America"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6622-415X","authenticated-orcid":false,"given":"Romain","family":"Madelaine","sequence":"additional","affiliation":[{"name":"MDI Biological Laboratory, Kathryn W. Davis Center for Regenerative Biology and Aging, Bar Harbor, Maine, United States of America"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026041110350795000_2025.02.16.638443v1.1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.123729"},{"key":"2026041110350795000_2025.02.16.638443v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05660"},{"key":"2026041110350795000_2025.02.16.638443v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)60763-7"},{"key":"2026041110350795000_2025.02.16.638443v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.abd.2019.09.023"},{"key":"2026041110350795000_2025.02.16.638443v1.5","doi-asserted-by":"publisher","DOI":"10.1159\/000468538"},{"key":"2026041110350795000_2025.02.16.638443v1.6","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a017046"},{"key":"2026041110350795000_2025.02.16.638443v1.7","doi-asserted-by":"publisher","DOI":"10.1242\/dev.123.1.369"},{"key":"2026041110350795000_2025.02.16.638443v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2010.388"},{"key":"2026041110350795000_2025.02.16.638443v1.9","doi-asserted-by":"publisher","DOI":"10.1002\/DVDY.24550"},{"key":"2026041110350795000_2025.02.16.638443v1.10","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0749.2006.00307.x"},{"key":"2026041110350795000_2025.02.16.638443v1.11","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.31.19560"},{"key":"2026041110350795000_2025.02.16.638443v1.12","doi-asserted-by":"publisher","DOI":"10.1126\/science.1116238"},{"key":"2026041110350795000_2025.02.16.638443v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2011.12.042"},{"key":"2026041110350795000_2025.02.16.638443v1.14","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0603114103"},{"key":"2026041110350795000_2025.02.16.638443v1.15","doi-asserted-by":"publisher","DOI":"10.1242\/dev.00461"},{"key":"2026041110350795000_2025.02.16.638443v1.16","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-0749.2003.00057.x"},{"key":"2026041110350795000_2025.02.16.638443v1.17","doi-asserted-by":"publisher","DOI":"10.1111\/pcmr.12970"},{"key":"2026041110350795000_2025.02.16.638443v1.18","doi-asserted-by":"publisher","DOI":"10.3390\/ijms10062440"},{"key":"2026041110350795000_2025.02.16.638443v1.19","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.7b00967"},{"key":"2026041110350795000_2025.02.16.638443v1.20","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1005244107"},{"key":"2026041110350795000_2025.02.16.638443v1.21","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-56017-5_3"},{"key":"2026041110350795000_2025.02.16.638443v1.22","doi-asserted-by":"crossref","unstructured":"Chang, W.-L. , Lee, W.-R. , Kuo, Y.-C. & Huang, Y.-H . Vitiligo: An Autoimmune Skin Disease and its Immunomodulatory Therapeutic Intervention. Front Cell Dev Biol 9, 797026 (2021).","DOI":"10.3389\/fcell.2021.797026"},{"key":"2026041110350795000_2025.02.16.638443v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.peptides.2009.04.025"},{"key":"2026041110350795000_2025.02.16.638443v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.3700438"},{"key":"2026041110350795000_2025.02.16.638443v1.25","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200214643"},{"key":"2026041110350795000_2025.02.16.638443v1.26","first-page":"1543","article-title":"Genetic and Genomic Pathways of Melanoma Development","volume":"12","year":"2021","journal-title":"Invasion and Metastasis. Genes (Basel)"},{"key":"2026041110350795000_2025.02.16.638443v1.27","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad2197"},{"key":"2026041110350795000_2025.02.16.638443v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2020.06.013"},{"key":"2026041110350795000_2025.02.16.638443v1.29","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.24005"},{"key":"2026041110350795000_2025.02.16.638443v1.30","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22115735"},{"key":"2026041110350795000_2025.02.16.638443v1.31","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0749.1995.tb00669.x"},{"key":"2026041110350795000_2025.02.16.638443v1.32","doi-asserted-by":"publisher","DOI":"10.1001\/archderm.1966.01600230093025"},{"key":"2026041110350795000_2025.02.16.638443v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/0738-081X(89)90061-8"},{"key":"2026041110350795000_2025.02.16.638443v1.34","doi-asserted-by":"publisher","DOI":"10.1271\/bbb.59.143"},{"key":"2026041110350795000_2025.02.16.638443v1.35","first-page":"263","article-title":"Evaluating the Safety and Efficacy of a Topical Formulation Containing Epidermal Growth Factor, Tranexamic Acid, Vitamin C, Arbutin, Niacinamide and Other Ingredients as Hydroquinone 4% Alternatives to Improve Hyperpigmentation: A Prospective, Randomized, Controlled Split Face Study","volume":"71","year":"2020","journal-title":"J Cosmet Sci"},{"key":"2026041110350795000_2025.02.16.638443v1.36","doi-asserted-by":"publisher","DOI":"10.1080\/10408440701638970"},{"key":"2026041110350795000_2025.02.16.638443v1.37","doi-asserted-by":"publisher","DOI":"10.2147\/CCID.S233185"},{"key":"2026041110350795000_2025.02.16.638443v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2006.06.015"},{"key":"2026041110350795000_2025.02.16.638443v1.39","doi-asserted-by":"publisher","DOI":"10.1111\/j.1473-2165.2008.00387.x"},{"key":"2026041110350795000_2025.02.16.638443v1.40","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1606"},{"key":"2026041110350795000_2025.02.16.638443v1.41","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0625.2009.01059.x"},{"key":"2026041110350795000_2025.02.16.638443v1.42","unstructured":"Khan, P. et al. Functional Agonists of the Apelin (APJ) Receptor. in Probe Reports from the NIH Molecular Libraries Program (National Center for Biotechnology Information (US), Bethesda (MD), 2010)."},{"key":"2026041110350795000_2025.02.16.638443v1.43","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.13758.019"},{"key":"2026041110350795000_2025.02.16.638443v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/nature12111"},{"key":"2026041110350795000_2025.02.16.638443v1.45","doi-asserted-by":"publisher","DOI":"10.1242\/dev.059345"},{"key":"2026041110350795000_2025.02.16.638443v1.46","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.11.8169"},{"key":"2026041110350795000_2025.02.16.638443v1.47","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.202000647"},{"key":"2026041110350795000_2025.02.16.638443v1.48","doi-asserted-by":"publisher","DOI":"10.1111\/1523-1747.ep12319351"},{"key":"2026041110350795000_2025.02.16.638443v1.49","doi-asserted-by":"publisher","DOI":"10.1080\/14756366.2020.1740691"},{"key":"2026041110350795000_2025.02.16.638443v1.50","doi-asserted-by":"crossref","unstructured":"Patel, N. & Shah, H . Exogenous Ochronosis from Skin-Lightening Cream. N Engl J Med 390, 254 (2024).","DOI":"10.1056\/NEJMicm2305739"},{"key":"2026041110350795000_2025.02.16.638443v1.51","doi-asserted-by":"publisher","DOI":"10.2147\/CCID.S396430"},{"key":"2026041110350795000_2025.02.16.638443v1.52","doi-asserted-by":"crossref","unstructured":"Qi, F. , Liu, F. & Gao, L . Janus Kinase Inhibitors in the Treatment of Vitiligo: A Review. Front Immunol 12, 790125 (2021).","DOI":"10.3389\/fimmu.2021.790125"},{"key":"2026041110350795000_2025.02.16.638443v1.53","doi-asserted-by":"publisher","DOI":"10.1007\/s13555-023-00892-5"},{"key":"2026041110350795000_2025.02.16.638443v1.54","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics14051001"},{"key":"2026041110350795000_2025.02.16.638443v1.55","first-page":"628","article-title":"Leprosy work at Ambilikkai, south India--a report","volume":"60","year":"1988","journal-title":"Indian J Lepr"},{"key":"2026041110350795000_2025.02.16.638443v1.56","doi-asserted-by":"publisher","DOI":"10.1080\/1744666X.2022.2014323"},{"key":"2026041110350795000_2025.02.16.638443v1.57","first-page":"797","article-title":"Pigmentation Disorders: Diagnosis and Management","volume":"96","year":"2017","journal-title":"Am Fam Physician"},{"key":"2026041110350795000_2025.02.16.638443v1.58","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2023.11.001"},{"key":"2026041110350795000_2025.02.16.638443v1.59","doi-asserted-by":"publisher","DOI":"10.1002\/aja.1002030302"},{"key":"2026041110350795000_2025.02.16.638443v1.60","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2019.10.004"},{"key":"2026041110350795000_2025.02.16.638443v1.61","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.21343"},{"key":"2026041110350795000_2025.02.16.638443v1.62","doi-asserted-by":"publisher","DOI":"10.1002\/etc.4055"},{"key":"2026041110350795000_2025.02.16.638443v1.63","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/21.5.1087"},{"key":"2026041110350795000_2025.02.16.638443v1.64","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0201-4"},{"key":"2026041110350795000_2025.02.16.638443v1.65","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3122"},{"key":"2026041110350795000_2025.02.16.638443v1.66","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt656"},{"key":"2026041110350795000_2025.02.16.638443v1.67","doi-asserted-by":"crossref","unstructured":"Love, M. I. , Huber, W. & Anders, S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15, 550 (2014).","DOI":"10.1186\/s13059-014-0550-8"},{"key":"2026041110350795000_2025.02.16.638443v1.68","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118"},{"key":"2026041110350795000_2025.02.16.638443v1.69","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0749.2007.00365.x"},{"key":"2026041110350795000_2025.02.16.638443v1.70","doi-asserted-by":"publisher","DOI":"10.1080\/14756360310001613094"},{"key":"2026041110350795000_2025.02.16.638443v1.71","doi-asserted-by":"publisher","DOI":"10.1038\/S41586-021-03819-2"},{"key":"2026041110350795000_2025.02.16.638443v1.72","doi-asserted-by":"publisher","DOI":"10.2174\/0929866526666191002111404"},{"key":"2026041110350795000_2025.02.16.638443v1.73","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20084"},{"key":"2026041110350795000_2025.02.16.638443v1.74","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks375"},{"key":"2026041110350795000_2025.02.16.638443v1.75","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.0c01480"},{"key":"2026041110350795000_2025.02.16.638443v1.76","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.10128"},{"key":"2026041110350795000_2025.02.16.638443v1.77","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1099-1352(199601)9:1<1::AID-JMR241>3.0.CO;2-6"},{"key":"2026041110350795000_2025.02.16.638443v1.78","doi-asserted-by":"publisher","DOI":"10.1111\/j.1747-0285.2007.00483.x"},{"key":"2026041110350795000_2025.02.16.638443v1.79","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20291"},{"key":"2026041110350795000_2025.02.16.638443v1.80","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.5b01211"},{"key":"2026041110350795000_2025.02.16.638443v1.81","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20290"},{"key":"2026041110350795000_2025.02.16.638443v1.82","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpcb.5b00689"},{"key":"2026041110350795000_2025.02.16.638443v1.83","doi-asserted-by":"publisher","DOI":"10.1517\/17460441.2015.1032936"},{"key":"2026041110350795000_2025.02.16.638443v1.84","doi-asserted-by":"publisher","DOI":"10.1021\/ct300418h"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.02.16.638443","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T17:35:13Z","timestamp":1775928913000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.02.16.638443"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,20]]},"references-count":84,"URL":"https:\/\/doi.org\/10.1101\/2025.02.16.638443","relation":{},"subject":[],"published":{"date-parts":[[2025,2,20]]},"subtype":"preprint"}}