Molecular Events in the Melanogenesis Cascade as Novel Melanoma-Targeted Small Molecules: Principle and Development

Simple Summary Melanin biosynthesis can be a unique pathway to identify novel anti-melanoma targeted molecules. In this approach, we specifically focused on the substrate of tyrosinase, which is highly expressed in malignant melanoma. Among the various forms of melanogenesis substrate synthesized, N-propionyl cysteaminylphenol was exploited to develop a melanoma-targeted chemo-immunotherapy drug because of its selective incorporation into melanoma cells and production of highly reactive molecules, which not only result in apoptotic cell death but also the generation of heat shock proteins by reacting with tyrosinase. Moreover, the drug was attached to magnetite nanoparticles in order to enable the heating of melanoma cells when they are exposed to an alternating magnetic field, which causes non-apoptotic cell death and further heat-shock protein generation (thermo-immunotherapy). Here, we review our synthesis of melanogenesis-based anti-melanoma molecules and development of selective chemo-thermo-immuno-therapy by combining these molecules with the magnetite-nanoparticles. We compare this strategy to other melanogenesis-based chemotherapy and thermal medicine systems, and discuss targeted therapies with immune checkpoint inhibitors for unresectable/metastatic melanoma. Abstract Malignant melanoma is one of the most malignant of all cancers. Melanoma occurs at the epidermo–dermal interface of the skin and mucosa, where small vessels and lymphatics are abundant. Consequently, from the onset of the disease, melanoma easily metastasizes to other organs throughout the body via lymphatic and blood circulation. At present, the most effective treatment method is surgical resection, and other attempted methods, such as chemotherapy, radiotherapy, immunotherapy, targeted therapy, and gene therapy, have not yet produced sufficient results. Since melanogenesis is a unique biochemical pathway that functions only in melanocytes and their neoplastic counterparts, melanoma cells, the development of drugs that target melanogenesis is a promising area of research. Melanin consists of small-molecule derivatives that are always synthesized by melanoma cells. Amelanosis reflects the macroscopic visibility of color changes (hypomelanosis). Under microscopy, melanin pigments and their precursors are present in amelanotic melanoma cells. Tumors can be easily targeted by small molecules that chemically mimic melanogenic substrates. In addition, small-molecule melanin metabolites are toxic to melanocytes and melanoma cells and can kill them. This review describes our development of chemo-thermo-immunotherapy based on the synthesis of melanogenesis-based small-molecule derivatives and conjugation to magnetite nanoparticles. We also introduce the other melanogenesis-related chemotherapy and thermal medicine approaches and discuss currently introduced targeted therapies with immune checkpoint inhibitors for unresectable/metastatic melanoma.