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- Title
A small molecule inhibitor of Mitf-E-box DNA binding and its depigmenting effect in melan-a cells.
- Authors
Um, J.-M.; Kim, H.J.; Lee, Y.; Choi, C.-H.; Hoang Nguyen, D.; Lee, H.-B.; Shin, J.-H.; Tai No, K.; Kim, E.-K.
- Abstract
Background Microphthalmia associated transcription factor (Mitf) is a key regulatory transcriptional factor of pigmentation-related genes including tyrosinase. Inhibition of tyrosinase transcription by blocking the binding of Mitf with its promoter E-box DNA can control the pigmentation. However, no such chemicals were reported so far. Objective To discover and evaluate the small molecule inhibitors of Mitf-E-box DNA. Methods Candidate chemicals were screened by virtual screening from pharmacophore data followed by Mitf E-box DNA protein chip. After selecting the chemical, its inhibitory activity on binding interaction between Mitf and E-box DNA, electrophoretic mobility shift assay (EMSA) was performed. To evaluate the depigmenting activity of Compound #17, cellular melanin assa, and Western blot were performed in melan-a cells. Results Among 27 chemicals selected from a pharmacophore data by virtual screening, Compound #17 was screened, which showed the most potent inhibitory activity against Mitf-E-box DNA binding in protein chip. EMSA results confirmed the specific inhibition of Compound #17 on Mitf-E-box DNA binding. In melan-a cells, Compound #17 reduced tyrosinase expression and melanin synthesis (62.5% at 25 μM). Conclusions The results show that Compound #17 is the first small molecule inhibitor of Mitf-E-box DNA binding with depigmenting activity.
- Subjects
CHEMICAL inhibitors; MICROPHTHALMIA-associated transcription factor; DNA-binding proteins; HUMAN skin color; PHENOL oxidase; TRANSCRIPTION factors; BIOLOGICAL assay
- Publication
Journal of the European Academy of Dermatology & Venereology, 2012, Vol 26, Issue 10, p1291
- ISSN
0926-9959
- Publication type
Article
- DOI
10.1111/j.1468-3083.2011.04286.x