Small molecule ML233 is a direct inhibitor of tyrosinase function and reduces melanoma proliferation

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, 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. Such inhibitors would also have potential as cancer therapies; melanomas are derived via malignant transformation of melanocytes, and inhibition of tyrosinase activity and/or melanogenesis has been suggested as a possible therapeutic strategy. However, despite decades of research, there is currently 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 in vivo and in vitro. We demonstrated that ML233 reduces melanin production in the zebrafish model with no observable significant toxic side effects, and in murine melanoma cells. We also showed that these effects are likely mediated through direct tyrosinase-ML233 interaction, i.e., binding of the ML233 molecule to the active site of the protein to inhibit its function. In addition, we showed that ML233 has the capacity to limit melanoma-cell proliferation in patient-derived xenograft organoids. Together, our results reveal that ML233 plays a dual role via inhibition of both melanin production and melanoma proliferation, and that 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. Overall design: Comparative gene expression profiling analysis of RNA-seq data for zebrafish apelin KO mutants vs wild-type at points 3hr and 24hr post appiication of drug ML233 at 0.5 µM with associated control