[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
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DOI：
10.1016/j.bcp.2007.05.028
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发表时间：
2007-09-01
影响因子：
5.8
通讯作者：
Hwang, Jae Sung
中科院分区：
文献类型：
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作者：
Na, Yong Joo;Baek, Heung Su;Hwang, Jae Sung
众所周知，c-kit与色素沉着以及肿瘤学靶蛋白有关。本研究的目的是发现一种调节c-kit活性的皮肤美白剂。我们已经开发了一个高通量的筛选系统，使用重组人c-kit蛋白。筛选了大约10，000种合成化合物对c-kit活性的影响。苯基咪唑磺酰胺衍生物在体外对c-kit磷酸化有抑制作用。进一步研究了一种衍生物[4-叔丁基苯基]-N-（4-咪唑-1-基苯基）磺酰胺（ISCK 03）对501 mel人黑素瘤细胞中干细胞因子（SCF）/c-kit细胞信号传导的影响。用ISCK 03预处理501 mel细胞可剂量依赖性地抑制SCF诱导的c-kit磷酸化。ISCK 03还抑制p44/42 ERK促分裂原活化蛋白激酶（MAPK）磷酸化，已知其参与SCF/c-kit下游信号传导。然而，ISCK 03不抑制肝细胞生长因子（HGF）诱导的p44/42 ERK蛋白的磷酸化。为了测定ISCK 03的体内效力，将其口服施用至脱毛的C57 BL/6小鼠。有趣的是，口服施用ISCK 03诱导新再生毛发的剂量依赖性脱色，并且这随着ISCK 03治疗的停止而逆转。最后，为了研究ISCK 03对SCF/c-kit信号传导的抑制作用是否消除UV诱导的色素沉着，将ISCK 03施加于褐色豚鼠皮肤上的UV诱导的色素斑。局部应用ISCK 03促进UV诱导的色素沉着过度斑点的脱色。Fontana-Masson染色分析显示在用ISCK 03处理的斑点中表皮黑色素减少。这些结果表明，苯基咪唑磺酰胺衍生物是有效的c-kit抑制剂，并可能被用作皮肤美白剂。(C)2007爱思唯尔公司All rights reserved.
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. (C) 2007 Elsevier Inc. All rights reserved.