L-765,314 Suppresses Melanin Synthesis by Regulating Tyrosinase Activity.

Abstract

Although melanin production is a key self-defense mechanism against ultraviolet radiation (UVR)-induced skin damage, uneven or excessive deposition of melanin causes hyperpigmentary disorders. Currently available whitening agents are unsatisfactory because of issues with efficacy and safety. To develop more effective depigmenting agents, we performed high-throughput melanin content assay screening using the B16F10 melanoma cell line and identified L-765,314 as a drug that suppressed melanin production in cultured melanocytes in a dose-dependent manner as well as cAMP- or 12-O-tetradecanoylphorbol 13-acetate (TPA)-stimulated melanin production without cytotoxicity. Interestingly, melanogenic gene expression was not altered by L-765,314. Rather, diminished melanin production by L-765,314 appeared to be caused by downregulation of tyrosinase activity via inhibition of protein kinase C (PKC). Because L-765,314 did not show any adverse effect in melanocytes, altogether our data suggest that L-765,314 could be a potential therapeutic candidate for skin hyperpigmentary disorders and further discovery of selective inhibitors targeting PKC might be a promising strategy for the development of depigmenting agents to treat hyperpigmentary disorders.

• Authors: Jinhwan Kim, Yo-Han Kim, Seunghyun Bang, Hanju Yoo, InKi Kim, Sung Eun Chang, Youngsup Song
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 24 Issue 4 (Feb 21 2019) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 30795539 (Publication Type: Journal Article)

Chemical References

• Bleaching Agents
• Enzyme Inhibitors
• L 765314
• Melanins
• Small Molecule Libraries
• Cyclic AMP
• Monophenol Monooxygenase
• Protein Kinase C
• Tetradecanoylphorbol Acetate
• Prazosin

Topics

• Animals
• Bleaching Agents (chemistry, pharmacology)
• Cyclic AMP (pharmacology)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemistry, pharmacology)
• Gene Expression Regulation
• High-Throughput Screening Assays
• Melanins (antagonists & inhibitors, biosynthesis)
• Melanoma, Experimental (genetics, metabolism, pathology)
• Mice
• Monophenol Monooxygenase (antagonists & inhibitors, genetics, metabolism)
• Prazosin (analogs & derivatives, chemistry, pharmacology)
• Protein Kinase C (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction
• Small Molecule Libraries (chemistry, pharmacology)
• Tetradecanoylphorbol Acetate (pharmacology)
• Tumor Cells, Cultured