1. Triazine-based tyrosinase inhibitors identified by chemical genetic screening
- Author
-
Jennifer K. Leung, Darren R. Williams, Li Ni-Komatsu, Sonya M. Khersonsky, Seth J. Orlow, Young-Tae Chang, and Jaeki Min
- Subjects
Tyrosinase ,Clinical Biochemistry ,Plant Science ,Melanocyte ,Binding, Competitive ,Chromatography, Affinity ,Levodopa ,Mice ,MART-1 Antigen ,Affinity chromatography ,Antigens, Neoplasm ,medicine ,Animals ,Genetic Testing ,Enzyme Inhibitors ,Binding site ,Cytotoxicity ,Cells, Cultured ,Melanins ,chemistry.chemical_classification ,Binding Sites ,Monophenol Monooxygenase ,Pigmentation ,Triazines ,Cell Biology ,Combinatorial chemistry ,Neoplasm Proteins ,Kinetics ,Protein Transport ,Enzyme ,medicine.anatomical_structure ,chemistry ,Biochemistry ,Melanocytes ,Agronomy and Crop Science ,Chemical genetics ,Function (biology) ,Developmental Biology - Abstract
Summary As most of the available depigmenting agents exhibit only modest activity and some exhibit toxicities that lead to adverse side effects after long-term usage, there remains a need for novel depigmenting agents. Chemical genetic screening was performed on cultured melanocytes to identify novel depigmenting compounds. By screening a tagged-triazine library, we identified four compounds, TGH11, TGD10, TGD39 and TGJ29, as potent pigmentation inhibitors with IC50 values in the range of 10 μM. These newly identified depigmenting compounds were found to function as reversible inhibitors of tyrosinase, the key enzyme involved in melanin synthesis. Tyrosinase was further confirmed as the cellular target of these compounds by affinity chromatography. Kinetic data suggest that all four compounds act as competitive inhibitors of tyrosinase, most likely competing with l-3,4-dihydroxyphenylalanine (l-DOPA) for binding to the DOPA-binding site of the enzyme. No effect on levels of tyrosinase protein, processing or trafficking was observed upon treatment of melanocytes with these compounds. Cytotoxicity was not observed with these compounds at concentrations up to 20 μM. Our data suggest that TGH11, TGD10, TGD39 and TGJ29 are novel potent tyrosinase inhibitors with potential beneficial effects in the treatment of cutaneous hyperpigmentation.
- Published
- 2005