PT  - JOURNAL ARTICLE
AU  - Ying, Weiwen
AU  - Du, Zhenjian
AU  - Sun, Lijun
AU  - Foley, Kevin P.
AU  - Proia, David A.
AU  - Blackman, Ronald K.
AU  - Zhou, Dan
AU  - Inoue, Takayo
AU  - Tatsuta, Noriaki
AU  - Sang, Jim
AU  - Ye, Shuxia
AU  - Acquaviva, Jamie
AU  - Ogawa, Luisa Shin
AU  - Wada, Yumiko
AU  - Barsoum, James
AU  - Koya, Keizo
TI  - Ganetespib, a Unique Triazolone-Containing Hsp90 Inhibitor, Exhibits Potent Antitumor Activity and a Superior Safety Profile for Cancer Therapy
AID  - 10.1158/1535-7163.MCT-11-0755
DP  - 2012 Feb 01
TA  - Molecular Cancer Therapeutics
PG  - 475--484
VI  - 11
IP  - 2
4099  - http://mct.aacrjournals.org/content/11/2/475.short
4100  - http://mct.aacrjournals.org/content/11/2/475.full
SO  - Mol Cancer Ther2012 Feb 01; 11
AB  - 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 sustained activity even with short exposure times. In vivo, ganetespib showed potent antitumor efficacy in solid and 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 μm from the microvasculature, to inhibit proliferation and induce apoptosis. Importantly, ganetespib showed no evidence of cardiac or liver toxicity. Taken together, this preclinical activity profile indicates that ganetespib may have broad application for a variety of human malignancies, and with select mechanistic and safety advantages over other first- and second-generation Hsp90 inhibitors. Mol Cancer Ther; 11(2); 475–84. ©2011 AACR.