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

作者：Um J M; Kim H J; Lee Y; Choi C H; Nguyen D Hoang; Lee H B; Shin J H; No K Tai; Kim E K^*

来源：Journal of the European Academy of Dermatology and Venereology, 2012, 26(10): 1291-1297.

DOI：10.1111/j.1468-3083.2011.04286.x

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 mu M). Conclusions The results show that Compound #17 is the first small molecule inhibitor of Mitf-E-box DNA binding with depigmenting activity.

• 出版日期2012-10