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Identification of Quinolines that Inhibit Melanogenesis by Altering Tyrosinase Family Trafficking

The Ronald O. Perelman Department of Dermatology and the Department of Cell Biology, New York University School of Medicine, New York, New York (L.N.-K., C.X.T., N.B., S.J.O.); and PTC Therapeutics, South Plainfield, New Jersey (G.C.)

A series of quinolines, including chloroquine and quinine, were identified as potent pigmentation inhibitors through screening a compound library in murine melanocytes. Structure-activity relationship analysis indicated that 4-substituted amino groups with a tertiary amine side chain, such as chloroquine, were associated with robust inhibitory activity. In contrast to many previously identified pigmentation inhibitors, these newly identified inhibitors had no effect on either the level or the enzymatic activity of tyrosinase, the rate-limiting enzyme in melanin production. Rather, our results showed that these quinolines inhibited melanogenesis by disrupting the intracellular trafficking of tyrosinase-related proteins and lysosome-associated membrane protein 1 (Lamp-1). In treated melanocytes, tyrosinase and tyrosinase-related protein 1 accumulated in Lamp-1-positive perinuclear organelles instead of melanosomes, thus preventing melanogenesis. The depigmenting abilities of chloroquine and quinine salicylate were assessed in a human skin equivalent model (MelanoDerm). Both compounds were considerably more effective than arbutin, a widely used lightening agent. Our results indicate that quinolines may be useful agents for "cosmeceutical" skin lightening and treatment of hyperpigmentation disorders.

Address correspondence to: Seth J. Orlow, Dermatology Room H-100, NYU School of Medicine, 560 First Avenue, New York, NY 10016. E-mail: seth.orlow{at}nyumc.org