A new 2-imino-1,3-thiazoline derivative, KHG22394, inhibits melanin synthesis in mouse B16 melanoma cells.

During our on-going attempts to develop a new skin-whitening agent, we identified a novel candidate compound KHG22394, a 2-imino-1,3-thiazoline derivative. Our data show that KHG22394 significantly inhibits melanin production in a dose-dependent manner, but that it does not directly inhibit tyrosinase, the rate limiting melanogenic enzyme. It has been reported that the activation of extracellular signal-regulated kinase (ERK) reduces melanin synthesis by downregulating microphthalmia-associated transcription factor (Mitf). Thus, we examined the effects of KHG22394 on the ERK pathway and found that it induced ERK and 90 kDa ribosomal S6 kinase (RSK-1) activation. Moreover, alpha-melanocyte-stimulating hormone (alpha-MSH) is known to increase melanin biosynthesis by increasing tyrosinase production, and here, we found that alpha-MSH-induced Mitf and tyrosinase increases were inhibited in B16 melanoma cells treated with KHG22394. These findings suggest that the hypopigmentary effect of KHG22394 results from the downregulation of Mitf and subsequently of tyrosinase, although KHG22394 did not inhibit tyrosinase activity directly. Our findings indicate that 2-imino-1,3-thiazoline derivatives are potential skin whitening agents.