生物活性

• 靶点	HSP90 IC50:4nM

• 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. Ganetespib is a novel HSP90 inhibitor which is a resorcinol-containing triazole compound unrelated to the first class of HSP90 inhibitors, geldanamycin, 17-AAG and 17-DMAG. As both AKT and KIT are the client protein of HSP90 and are stabilized by it, inhibition of HSP90 by 100nM Ganetespib for 24h caused downregulation of both KIT and AKT only on protein level in BR can C2 cells, as well as a disruption of the association of HSP90 with Kit. Meanwhile, as upregulation of HSP70 is a consequence of HSP90 inhibition, exposure to Ganetespib also caused an induction of HSP70 expression in cells. STA-9090 led to 72-hour growth inhibition of malignant canine mast cell lines C2 and BR with IC50 values of 19nM and 4nM, respectively, much lower than 17-AAG (IC50=948nm (C2) and 44 nm (BR)). Treatment with Ganetespib caused cell apoptosis, shown as increased Annexin V-phycoerythrin [PE] /7-amino-actinomycin D (7-AAD) and increased Sub-G1 level in C2, BR, and BMCMC treated with 100nM Ganetespib for 24 or 48h, cleaved PARP induced by 100 or 1000nM Ganetespib for 24h in BR and C2 cells, and increased caspase3/7 in C2 cells treated with 50 or 75nM Ganetespib for 24h. Intravenous injection with Ganetespib at concentration of 25mg/kg, 3 days on and 2 days off, for 17 days significantly inhibited tumor growth in the C2 xenograft model^[1].
• 作用机制Ganetespib can bind in the ATP-binding domain at the N-terminus of HSP90. ^[1]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  35612	-	Growth Inhibition Assay	-	IC50=38 nM	24784839
  5637	-	Growth Inhibition Assay	-	IC50=44 nM	24784839
  639-V	-	Growth Inhibition Assay	-	IC50=10 nM	24784839

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• 动物研究
  剂量	Mice (i.v.): min = 25 mg/kg[2], max = 100 mg/kg[3] (i.v.)
  给药途径	i.v.
  动物药代数据	Animal Rats[4] Dose 20 mg/kg Administration i.v. T1/2 6.4 h Tmax 0.083 h Cmax 110 μM AUC 36.1 μM·h

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01042379	Breast Neoplasms ... more >> Breast Cancer Breast Tumors Collapse <<	Phase 2	Recruiting	-	-
  NCT01227018	Adenocarcinoma of the Pancreas... more >> Recurrent Pancreatic Cancer Stage IV Pancreatic Cancer Collapse <<	Phase 2	Terminated(interim analysis fo... more >>und the study drug to be ineffective) Collapse <<	-	United States, Tennessee ... more >> The Jones Clinic Memphis, Tennessee, United States, 38138 Vanderbilt-Ingram Cancer Center Nashville, Tennessee, United States, 37232-6838 Collapse <<
  NCT01227018	-	-	Terminated(interim analysis fo... more >>und the study drug to be ineffective) Collapse <<	-	-

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• 参考文献

• [1] Lin TY, Bear M, et al. The novel HSP90 inhibitor STA-9090 exhibits activity against Kit-dependent and -independent malignant mast cell tumors. Exp Hematol. 2008;36(10):1266-77.

  [2] Shimamura T, Perera SA, et al. Ganetespib (STA-9090), a nongeldanamycin HSP90 inhibitor, has potent antitumor activity in in vitro and in vivo models of non-small cell lung cancer. Clin Cancer Res. 2012 Sep 15;18(18):4973-85.

  [3] Nagaraju GP, Mezina A, et al. Targeting the Janus-activated kinase-2-STAT3 signalling pathway in pancreatic cancer using the HSP90 inhibitor ganetespib. Eur J Cancer. 2016 Jan;52:109-19.

  [4] Zhou D, Liu Y, et al. A rat retinal damage model predicts for potential clinical visual disturbances induced by Hsp90 inhibitors. Toxicol Appl Pharmacol. 2013 Dec 1;273(2):401-9.