selleck产品在文献中的引用: 
Nat Biotechnol,2013,31(10):898-907 
Cell,2013,154(5):1036-46 
Cell,2013,153(4):840-54 
Science,2013,339(6120):700-4



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生物活性
产品描述
Ganetespib (STA-9090)是一种HSP90抑制剂，作用于OSA 8种细胞，IC50为4 nM，诱导OSA细胞凋亡，而对正常的成骨细胞无作用；是STA-1474的活性代谢物。
靶点
HSP90
 
 
 
 
 
IC50
4 nM [1]
 
 
 
 
 
体外研究
The 50% inhibitory concentrations (IC50) for Ganetespib against malignant mast cell lines are 10-50 times lower than that for 17-AAG, indicating that triazolone class of HSP90 inhibitors likely exhibits greater potency than geldanamycin based inhibitors. [1] Ganetespib inhibits MG63 cell lines with IC50 of 43 nM. [1] Ganetespib binds to the ATP-binding domain at the N-terminus of Hsp90 and serves as a potent Hsp90 inhibitor by causing degradation of multiple oncogenic Hsp90 client proteins including HER2/neu, mutated EGFR, Akt, c-Kit, IGF-1R, PDGFRα, Jak1, Jak2, STAT3, STAT5, HIF-1α, CDC2 and c-Met as well as Wilms tumor 1. [2] Ganetespib, at low nanomolar concentrations, potently arrests cell proliferation and induces apoptosis in a wide variety of human cancer cell lines, including many receptor tyrosine kinase inhibitor- and tanespimycin-resistant cell lines. Ganetespib exhibits potent cytotoxicity in a range of solid and hematologic tumor cell lines, including those that express mutated kinases that confer resistance to small-molecule tyrosine kinase inhibitors. [3] Ganetespib treatment rapidly caused the degradation of known Hsp90 client proteins, exhibits superior potency to the ansamycin inhibitor 17-AAG, and shows sustained activity even with short exposure times.[3] In anohter study, Ganetespib induces apoptosis of malignant canine mast cell lines. Ganetespib is active at significantly lower concentrations for C2 and BR canine malignant mast cells with IC50 of 19 and 4 nM, respectively, while 17-AAG inhibits C2 and BR canine malignant mast cells with IC50 of 958 and 44 nM, respectively. [4] Both the expression of WT and mutant Kit are downregulated by 100 nM Ganetespib after 24 hours in all lines treated including C2 and BMCMCs cells. However, no effects on PI3K or HSP90 expression are observed following treatment with Ganetespib.[4]
体内研究
Administration of Ganetespib leads to significant tumor shrinkage in several tumor xenograft models in mice and appears to be less toxic. Furthermore Ganetespib demonstrated better tumor penetration compared with tanespimycin.[2] Ganetespib inhibits in vivo tumor growth in both malignant mast cell and OSA xenograft models. Ganetespib significantly inhibits tumor growth when dosed with two repeating cycles of 25 mg/kg/day for 3 days, with a %T/C value of 18. Ganetespib is well-tolerated, with the vehicle and Ganetespib groups having average bodyweight changes relative to the start of the study of +0.3% and -8.1% on day 17, respectively.[4]
临床实验
Ganetespib has entered in a phase II clinical trials in the treatment of non small cell lung cancer.
特征
 
细胞试验: [1]
细胞系
OSA cells
浓度
0.001-1μM
处理时间
5 days
方法
A total of 1.5 × 103 OSA cells are seeded in 96-well plates in 10% serum-containing complete medium and incubated overnight to determine the 50% inhibitory concentrations. Plates are, harvested at day 5 following 0.001, 0.005, 0.01, 0.05, 0.1, 0.5 and 1 μM Ganetespib, treatment and analyzed. Fluorescence measurements are made using a plate reader with excitation at 485 nm and emission detection at 530 nm. Relative cell number is calculated as a percentage of the control wells: absorbance of sample/absorbance of DMSO treated cells × 100.
动物实验: [4]
动物模型
Female severe combined immune-deficient (SCID) mice
配制
In DMSO and diluted 1:10 with 20% Cremophor RH 40
剂量
25 mg/kg/day for 3 days
给药处理
Tail vein injection
溶解度
1% DMSO/30% polyethylene glycol/1% Tween 80, 30 mg/mL
参考文献
[1] McCleese Jk, et al. Int J Cancer. 2009, 125(12), 2792-2801.
[2] Wang Y, et al. Curr Opin Investig Drugs. 2010 , 11(12), 1466-1476.
[3] Ying W, et al. Mol Cancer Ther. 2012, 11(2), 475-484.
[4] Lin TY, et al. Exp Hematol. 2008, 36(10), 1266-1277.