TY - JOUR
T1 - A small molecule inhibitor of Mitf-E-box DNA binding and its depigmenting effect in melan-a cells
AU - Um, J. M.
AU - Kim, H. J.
AU - Lee, Y.
AU - Choi, C. H.
AU - Hoang Nguyen, D.
AU - Lee, H. B.
AU - Shin, J. H.
AU - Tai No, K.
AU - Kim, E. K.
PY - 2012/10
Y1 - 2012/10
N2 - 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.
AB - 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.
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U2 - 10.1111/j.1468-3083.2011.04286.x
DO - 10.1111/j.1468-3083.2011.04286.x
M3 - Article
C2 - 21957942
AN - SCOPUS:84866259036
SN - 0926-9959
VL - 26
SP - 1291
EP - 1297
JO - Journal of the European Academy of Dermatology and Venereology
JF - Journal of the European Academy of Dermatology and Venereology
IS - 10
ER -
