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

ABSTRACT: 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.

ORGANISM(S): Danio rerio

PROVIDER: GSE268076 | GEO | 2024/05/22

REPOSITORIES: GEO

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Project description:Dietary tyrosine regulating melanoma progression has been well-recognized. However, whether tyrosine-based melanin anabolism contributes to pulmonary and cerebral organotropic colonization of melanoma remains elusive. Furthermore, how to inhibit multi-organ metastasis by interfering tyrosinase activity of melanoma cells and function of immunocytes needs to be designed and validated. Patients derived melanoma cells and mouse B16 melanoma cells with different pigment were employed in this investigation. Tyrosine content dynamics in tumors and multiple organs during the melanoma progression were monitored, and tyrosine-based melanin synthesis ability of melanoma cells derived from multi-organ were detected. Additionally, we also adopted the RNA-seq, flowcytometry, real-time PCR and composite metastasis mouse model to analyze organotropic colonization and to design therapeutic strategies. B16 melanoma cells with high activity of tyrosinase and sensitivity of tyrosine utilization for melanin synthesis (Tyr-H cells) easily colonized in the lung, while B16 melanoma cells without above characteristics (Tyr-L cells) exhibited potent proliferation in the brain. Mechanistically, Tyr-H cells recruited and trained neutrophils and macrophages to build up the pulmonary metastatic niche dependent on highly secreted CXCL1 and CXCL2 and an excess melanosome accumulation-induced cell death. Tyr-L cells enhanced PD-L1 expression in tumor-infiltrated macrophages when they are progressing in the brain. Accordingly, intervention of tyrosinase activity (2-Ethoxybenzamide or hydroquinone), together with inhibitors to phagocytosis (GSK343) or chemotaxis (SB225002) suppress organotropic colonization and significantly improve the survival of immune checkpoint blockade (PD1 antibody) treated melanoma bearing mice. The heterogeneity of melanoma cells in utilization of tyrosine is associated with organotropic colonization, providing the basis for developing strategies to combat melanoma and prevent their metastasis.

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

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