1. Academic Validation
  2. [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

[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

  • Biochem Pharmacol. 2007 Sep 1;74(5):780-6. doi: 10.1016/j.bcp.2007.05.028.
Yong Joo Na 1 Heung Su Baek Soo Mi Ahn Hyun Jung Shin Ih-Seop Chang Jae Sung Hwang
Affiliations

Affiliation

  • 1 Skin Research Institute, AMOREPACIFIC R&D Center, 314-1 Bora-dong, Giheung-gu, Yongin-si, 446-729, Republic of Korea.
Abstract

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.

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