生物活性 | |||
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描述 | HSP90 (heat shock protein 90) is a cellular ubiquitous molecular chaperone responsible for promoting the conformational mutation and stabilization of several client oncoproteins, including Met, B-Raf, p53, Akt, and Kit, function of which is required by tumor cells to maintain appropriate client protein expression necessary for proliferation and survival. SNX-2112 and its prodrug SNX-5422 are HSP90 inhibitors with IC50 value of 30nM (measured by ATP displacement assay). Treatment with SNX-2112 led to downregulation of protein level of HER2 and AKT signaling, in a time-dependent (at 1μM with 48h) and dose-dependent (<1μM for 24h) in BT-474 cells. SNX-2112 inhibited cell proliferation of a panel of breast, lung, and ovarian cancer cell lines with IC50 values ranging in 10-50nM, and also caused a profound mitotic block in MDA-468 cells at 1μM for 48h. Consistent with apoptosis induced by SNX-2112, increased cleaved PARP and decreased CDK1 can also be observed in BT-474 cells treated with SNX-2112. A single dose of 50m/kg SNX-2112 can repeat the effect on the client protein in vivo, with most potency at 10h post dose. Oral administration of SNX-2112 at dose of 50mg/kg, 5 days per week, could significantly inhibit tumor growth in BT474 tumor xenografts after treatment for 4 weeks, and in H1650 tumor xenografts after treatment for 37 days[1]. | ||
作用机制 | SNX-2112 binds to the amino-terminal ATP site of Hsp90.[1] |
细胞研究 | |||||
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细胞系 | 浓度 | 检测类型 | 检测时间 | 活性说明 | 数据源 |
A375 cells | Function assay | 24 h | Inhibition of Hsp90 in human A375 cells assessed as pS6 degradation after 24 hrs by high content screening, IC50=0.001 μM | 19552433 | |
AU565 cells | Function assay | 24 h | Inhibition of Hsp90 in human AU565 cells assessed as pERK degradation after 24 hrs by high content screening, IC50=0.041 μM | 19552433 | |
HCT15 cells | Proliferation assay | 72-144 h | Antiproliferative activity against human HCT15 cells after 72 to 144 hrs by cyquant DNA dye method, IC50=0.052 μM | 19552433 |
实验方案 | |||
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1mg | 5mg | 10mg | |
1 mM 5 mM 10 mM |
2.15mL 0.43mL 0.22mL |
10.76mL 2.15mL 1.08mL |
21.53mL 4.31mL 2.15mL |
参考文献 |
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