Ganetespib 888216-25-9

STA-9090;STA9090
分子式：C20H20N4O3   分子量：364.4
 
產(chǎn)品描述
Ganetespib是HSP90抑制劑，作用于OSA 8種細(xì)胞，IC50為4 nM,誘導(dǎo)OSA細(xì)胞凋亡，而正常的成骨細(xì)胞不會(huì)受到影響;是STA-1474的活性代謝物。
靶點(diǎn)
HSP90
         
IC50
4 nM
         
體外研究
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.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.
體內(nèi)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.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.
溶解性
DMSO 40 mg/mL，水 <1 mg/mL，乙醇 9 mg/mL
穩(wěn)定性
2年 -20°C粉狀，6月-80°C溶于DMSO