Abstract
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.
Highlights
Hsp90 is a molecular chaperone that regulates the posttranslational folding, stability and function of its protein substrates, many of which play critical roles in cell growth, differentiation, and survival [1, 2]
Ganetespib is a novel resorcinolic triazolone compound that is structurally distinct to the first-generation ansamycin Hsp90 inhibitors
We have obtained the cocrystal structure of ganetespib bound to the closed conformation of the Hsp90 N-terminus (Fig. 1B); we anticipate that ganetespib can access the ATP pocket in the open conformation based on computational analysis
Summary
Hsp is a molecular chaperone that regulates the posttranslational folding, stability and function of its protein substrates (client proteins), many of which play critical roles in cell growth, differentiation, and survival [1, 2]. The Hsp machinery serves as a biochemical buffer for a number of oncogenic signaling proteins causally implicated in a variety of tumors [3, 4]. Often, these oncoproteins are expressed as mutant forms that are reliant. A unique characteristic of targeting Hsp is that inhibition results in the combinatorial blockade of multiple signal transduction cascades, thereby potentially bypassing pathway redundancies often found in cancer cells [9,10,11]. Hsp represents an attractive molecular target for the development of novel cancer therapeutics [4, 11, 12]
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