Ganetespib (CAS 888216-25-9)

Ganetespib has an IC50 value 10–50 times lower than that for 17-AAG against malignant mast cell lines, indicating that the triazolone class of HSP90 inhibitors is likely more potent than geldanamycin based inhibitors. Ganetespib inhibits MG63 cell lines (IC50 of 43 nM). Ganetespib binds to the ATP-binding domain at the N-terminus of Hsp90 and potently inhibits Hsp90 by inducig 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. At nanomolar concentrations, Ganetespib potently arrests cell proliferation and induces apoptosis in a wide variety of human cancer cell lines, including many receptor tyrosine kinase inhibitors and tanespimycin-resistant cell lines. Ganetespib is a potent cytotoxin 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 rapidly causes 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.