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 (A(3)B(5)), 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 A(3)B(5) in melanin production. Our results showed that A(3)B(5) had no effect on the production and activity of tyrosinase, an enzyme involved in melanogenesis. However, A(3)B(5) 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 A(3)B(5) may occur through proteasomal degradation because the A(3)B(5)-induced TRP-2 downregulation was inhibited by the ubiquitination inhibitor, MG-132. In addition, A(3)B(5) 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 A(3)B(5) downregulates melanin production and melanoma cell growth via proteosomal degradation of TRP-2 and suggest that A(3)B(5) can be a possible therapeutic agent that effectively regulates both hyperpigmentation and melanoma growth in the skin.