product name Ganetespib (STA-9090)
Description: Ganetespib (also known as STA-9090) is a synthetic small-molecule HSP90 inhibitor with IC50 of 4 nM in OSA 8 cells, it induces apoptosis of OSA cells while normal osteoblasts are not affected; it is the active metabolite of STA-1474. Ganetespib binds to and inhibits Hsp90, resulting in the proteasomal degradation of oncogenic client proteins, the inhibition of cell proliferation and the elevation of heat shock protein 72 (Hsp72); it may inhibit the activity of multiple kinases, such as c-Kit, EGFR, and Bcr-Abl, which as client proteins depend on functional HsP90 for maintenance.
References: Int J Cancer. 2009 Dec 15;125(12):2792-801; Curr Opin Investig Drugs. 2010 Dec;11(12):1466-76.
364.4
Formula
C20H20N4O3
CAS No.
888216-25-9
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 40 mg/mL (109.8 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
1% DMSO+30% polyethylene glycol+1% Tween 80: 30 mg/mL
Synonyms
STA-9090
other peoduct :
| In Vitro |
In vitro activity: 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. Ganetespib inhibits MG63 cell lines with IC50 of 43 NM. 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. 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. 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. 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. 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. Kinase Assay: Cell Assay: 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. |
|---|---|
| In Vivo | 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. 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. |
| Animal model | Female severe combined immune-deficient (SCID) mice |
| Formulation & Dosage | Dissolved in DMSO and diluted 1:10 with 20% Cremophor RH 40; 25 mg/kg; Tail vein injection |
| References | Int J Cancer. 2009 Dec 15;125(12):2792-801; Curr Opin Investig Drugs. 2010 Dec;11(12):1466-76. |
