Preclinical Development Ganetespib, a Unique Triazolone-Containing Hsp90 Inhibitor, Exhibits Potent Antitumor Activity and a Superior Safety Profile for Cancer Therapy

Targeted inhibition of the molecular chaperone Hsp90 results in the simultaneous blockade of multiple oncogenic signaling pathways and has, thus, emerged as an attractive strategy for the development of novel cancer therapeutics. Ganetespib (formerly known as STA-9090) is a unique resorcinolic triazolone inhibitor of Hsp90 that is currently in clinical trials for a number of human cancers. In the present study, we showed that ganetespib exhibits potent in vitro 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 induced the degradation of known Hsp90 client proteins, displayed superior potency to the ansamycin inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), and exhibited sustainedactivity evenwith short exposure times. In vivo, ganetespib showedpotent antitumorefficacy in solidand hematologic xenograft models of oncogene addiction, as evidenced by significant growth inhibition and/or regressions. Notably, evaluation of the microregional activity of ganetespib in tumor xenografts showed that ganetespib was efficiently distributed throughout tumor tissue, including hypoxic regions >150 mm from the microvasculature, to inhibit proliferation and induce apoptosis. Importantly, ganetespib showedno evidence of cardiacor liver toxicity. Taken together, this preclinical activityprofile indicates that ganetespibmayhavebroad application for a variety of humanmalignancies, and with select mechanistic and safety advantages over other firstand second-generation Hsp90 inhibitors. Mol Cancer Ther; 11(2); 475–84. 2011 AACR.