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]
SNX-2112 细胞研究
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
HT-29 cells
Proliferation assay
72-144 h
Antiproliferative activity against human HT-29 cells after 72 to 144 hrs by cyquant DNA dye method, IC50=0.003 μM
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
HT-29 cells
Proliferation assay
72-144 h
Antiproliferative activity against human HT-29 cells after 72 to 144 hrs by cyquant DNA dye method, IC50=0.003 μM
19552433
human SK-MEL-5 cells
Proliferation assay
72-144 h
Antiproliferative activity against human SK-MEL-5 cells after 72 to 144 hrs by cyquant DNA dye method, IC50=0.006 μM
19552433
human SW620 cells
Proliferation assay
72-144 h
Antiproliferative activity against human SW620 cells after 72 to 144 hrs by cyquant DNA dye method, IC50=0.003 μM
19552433
K562 cells
Proliferation assay
72-144 h
Antiproliferative activity against human K562 cells after 72 to 144 hrs by cyquant DNA dye method, IC50=0.006 μM
19552433
LNCAP cells
Proliferation assay
72-144 h
Antiproliferative activity against human LNCAP cells after 72 to 144 hrs by cyquant DNA dye method, IC50=0.003 μM
19552433
MCF7 cells
Function assay
Inhibition of HSP90alpha in human MCF7 cells assessed as degradation of Her-2, EC50=0.019 μM
22938030
MDA-MB-231 cells
Proliferation assay
72-144 h
Antiproliferative activity against human MDA-MB-231 cells after 72 to 144 hrs by cyquant DNA dye method, IC50=0.006 μM
19552433
MRC5 cells
Cytotoxicity assay
48 h
Cytotoxicity against human MRC5 cells after 48 hrs by MTT assay, CC50=21.34 μM
22704890
NCI-H460 cells
Proliferation assay
72-144 h
Antiproliferative activity against human NCI-H460 cells after 72 to 144 hrs by cyquant DNA dye method, IC50=0.018 μM
19552433
PC3 cells
Proliferation assay
72-144 h
Antiproliferative activity against human PC3 cells after 72 to 144 hrs by cyquant DNA dye method, IC50=0.017 μM
19552433
sf9 cells
Function assay
3 h
Binding affinity to human N-terminal polyHis-tagged HSP90beta (D9 to E236) expressed in insect sf9 cells after 3 hrs by fluorescence polarization assay, Ki=0.006 μM
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