tcsc0697 Ganetespib

Ganetespib is a unique non-geldanamycin heat shock protein 90 (HSP90) inhibitor, with antitumor activity.

IC50 & Target: HSP90^[1]

In Vitro: Ganetespib causes depletion of receptor tyrosine kinases, extinguishing of downstream signaling, inhibition of proliferation and induction of apoptosis with IC₅₀ values ranging 2-30 nM in genomically-defined NSCLC cell lines. Ganetespib is also approximately 20-fold more potent in isogenic Ba/F3 pro-B cells rendered IL-3 independent by expression of EGFR and ERBB2 mutants^[1]. Ganetespib exhibits potent in vitro cytotoxicity in a range of solid and hematologic tumor cell lines, induces the degradation of known Hsp90 client proteins, displays superior potency to the ansamycin inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG)^[2]. Ganetespib is a potent HSP90 inhibitor, and shown to kill canine tumor cell lines in vitro^[3]. Ganetespib possesses superior JAK/STAT inhibitory activity to both P6 and 17-AAG in terms of potency or duration of response in the HEL92.1.7 cells^[4].

In Vivo: Ganetespib (125 mg/kg, i.v.) accumulates in tumors relative to normal tissues and displays greater in vivo efficacy than 17-AAG without increased toxicity and inhibits proliferation and induces apoptosis in parallel with EGFR depletion in NCI-H1975 xenografts^[1]. Ganetespib (100, 125, 150 mg/kg, i.v.) shows potent antitumor efficacy in solid and hematologic xenograft models of oncogene addiction, as evidenced by significant growth inhibition and/or regressions^[2].