N-(3,5-Dimethylphenyl)-3-Methoxybenzamide (A3B5) Targets TRP-2 and Inhibits Melanogenesis and Melanoma Growth

Melanin protects the skin from harmful environmental factors such as UV light. However, excessive melanin production induces hyperpigmentation. Previously, N-(3,5-dimethylphenyl)-3-methoxybenzamide (A3B5), a biaryl amide derivative, was identified for its ability to inhibit melanin production. However, its detailed mechanism of action has not been investigated. We elucidated the inhibitory mechanisms of A3B5 in melanin production. Our results showed that A3B5 had no effect on the production and activity of tyrosinase, an enzyme involved in melanogenesis. However, A3B5 markedly decreased both constitutively expressed and UVB-induced tyrosinase-related protein 2 (TRP-2), which plays an important role along with tyrosinase in melanogenesis. The TRP-2 downregulation caused by A3B5 may occur through proteasomal degradation because the A3B5-induced TRP-2 downregulation was inhibited by the ubiquitination inhibitor, MG-132. In addition, A3B5 inhibited the proliferation of melanocytes and melanoma cells by arresting cells in the G1 stage of the cell cycle and moderately suppressed tumor growth in vivo. Taken together, our results indicate that A3B5 downregulates melanin production and melanoma cell growth via proteosomal degradation of TRP-2 and suggest that A3B5 can be a possible therapeutic agent that effectively regulates both hyperpigmentation and melanoma growth in the skin.