[4-t-butylphenyl]-N-(4-imidazol-1-yl phenyl)sulfonamide (ISCK03) inhibits SCF/c-kit signaling in 501mel human melanoma cells and abolishes melanin production in mice and brownish guinea pigs.
It is well known that c-kit is related to pigmentation as well as to the oncology target protein. The objective of this study was to discover a skin-whitening agent that regulates c-kit activity. We have developed a high-throughput screening system using recombinant human c-kit protein. Approximately 10,000 synthetic compounds were screened for their effect on c-kit activity. Phenyl-imidazole sulfonamide derivatives showed inhibitory activity on c-kit phosphorylation in vitro. The effects of one derivative, [4-t-butylphenyl]-N-(4-imidazol-1-yl phenyl)sulfonamide (ISCK03), on stem-cell factor (SCF)/c-kit cellular signaling in 501mel human melanoma cells were examined further. Pretreatment of 501mel cells with ISCK03 inhibited SCF-induced c-kit phosphorylation dose dependently. ISCK03 also inhibited p44/42 ERK mitogen-activated protein kinase (MAPK) phosphorylation, which is known to be involved in SCF/c-kit downstream signaling. However ISCK03 did not inhibit hepatocyte growth factor (HGF)-induced phosphorylation of p44/42 ERK proteins. To determine the in vivo potency of ISCK03, it was orally administered to depilated C57BL/6 mice. Interestingly, oral administration of ISCK03 induced the dose-dependent depigmentation of newly regrown hair, and this was reversed with cessation of ISCK03 treatment. Finally, to investigate whether the inhibitory effect of ISCK03 on SCF/c-kit signaling abolished UV-induced pigmentation, ISCK03 was applied to UV-induced pigmented spots on brownish guinea pig skin. The topical application of ISCK03 promoted the depigmentation of UV-induced hyperpigmented spots. Fontana-Masson staining analysis showed epidermal melanin was diminished in spots treated with ISCK03. These results indicate that phenyl-imidazole sulfonamide derivatives are potent c-kit inhibitors and might be used as skin-whitening agents.
Skin Research Institute, AMOREPACIFIC R&D Center, 314-1 Bora-dong, Giheung-gu, Yongin-si, 446-729, Republic of Korea.
Yong Joo
YJ
Na
Heung Su
HS
Baek
Soo Mi
SM
Ahn
Hyun Jung
HJ
Shin
Ih-Seop
IS
Chang
Jae Sung
JS
Hwang
D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation; D006168:Guinea Pigs; D006801:Humans; D017495:Hyperpigmentation / Q000188:drug therapy; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D008543:Melanins / Q000096:biosynthesis*; D008545:Melanoma / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D010766:Phosphorylation; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*
C528178:4-t-butylphenyl-N-(4-imidazol-1-ylphenyl)sulfonamide; D007093:Imidazoles; D008543:Melanins; D013449:Sulfonamides; D019009:Proto-Oncogene Proteins c-kit