Ganetespib (STA 9090) is a potent, second generation small-molecule inhibitor of HSP90 (IC50=4 nM).
Ganetespib blocks the ability of HSP90 to bind to biotinylated geldanamycin and disrupts the association of HSP90 with its cochaperone, p23, more potently than 17-AAG.
Ganetespib causes depletion of receptor tyrosine kinases, extinguishing of downstream signaling, inhibition of proliferation and induction of apoptosis with IC50 of 2-30 nM, in NSCLC cell lines.
Ganetespib is also approximately 20-fold more potent than 17-AAG in isogenic Ba/F3 pro-B cells rendered IL-3 independent by expression of EGFR and ERBB2 mutants.
Ganetespib binds to the ATP-binding domain at the N-terminus of Hsp90 and acts as a potent Hsp90 inhibitor by inducing 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, c-Met, and Wilms' tumor 1.