A small molecule inhibitor of Mitf-E-box DNA binding and its depigmenting effect in melan-a cells

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, n...

Full description

Saved in:
Bibliographic Details
Published in:Journal of the European Academy of Dermatology and Venereology 2012-10, Vol.26 (10), p.1291-1297
Main 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.
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Blotting, Western
Cell Line
Cell Line, Transformed
DNA - metabolism
DNA Primers
Electrophoretic Mobility Shift Assay
Humans
Mice
Microphthalmia-Associated Transcription Factor - metabolism
Small Molecule Libraries
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0926-9959
1468-3083
DOI:10.1111/j.1468-3083.2011.04286.x