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Ganetespib, a unique triazolone-containing Hsp90 inhibitor, exhibits potent antitumor activity and a superior safety profile for cancer therapy
- Source :
- Molecular cancer therapeutics. 11(2)
- Publication Year :
- 2011
-
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. Mol Cancer Ther; 11(2); 475–84. ©2011 AACR.
- Subjects :
- Male
Cancer Research
Cell Survival
Lactams, Macrocyclic
Blotting, Western
Ganetespib
Mice, Nude
Antineoplastic Agents
Apoptosis
HL-60 Cells
Mice, SCID
Pharmacology
Biology
Crystallography, X-Ray
Hsp90 inhibitor
Rats, Sprague-Dawley
chemistry.chemical_compound
Mice
In vivo
Cell Line, Tumor
Neoplasms
Benzoquinones
Animals
Humans
HSP90 Heat-Shock Proteins
Kinase
Heart
Triazoles
Oncogene Addiction
Hsp90
Xenograft Model Antitumor Assays
Rats
Oncology
chemistry
biology.protein
Female
Rabbits
Growth inhibition
Chemical and Drug Induced Liver Injury
K562 Cells
Tyrosine kinase
Subjects
Details
- ISSN :
- 15388514
- Volume :
- 11
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Molecular cancer therapeutics
- Accession number :
- edsair.doi.dedup.....fd2269c7212dff5e3d97523a8f2b2539