The novel oral Hsp90 inhibitor NVP-HSP990 exhibits potent and broad-spectrum antitumor activities in vitro and in vivo
| Autor: | Nancy Pryer, Daniel Menezes, Zhenhai Gao, Pietro Taverna, Duhl David, Michael Rugaard Jensen, Guoying Karen Yu, Darrin Stuart, William R. Sellers, Timothy D. Machajewski, Tinya Abrams |
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| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
Metabolic Clearance Rate Pyridones Blotting Western Administration Oral Mice Nude Antineoplastic Agents Apoptosis Mice SCID Biology Pharmacology Hsp90 inhibitor Inhibitory Concentration 50 Mice Downregulation and upregulation immune system diseases In vivo Cell Line Tumor Neoplasms Animals Humans Protein Isoforms HSP90 Heat-Shock Proteins Receptor Cell Proliferation Dose-Response Relationship Drug Molecular Structure Kinase Cell growth virus diseases Xenograft Model Antitumor Assays In vitro Tumor Burden Pyrimidines Oncology Cell culture Area Under Curve |
| Zdroj: | Molecular cancer therapeutics. 11(3) |
| ISSN: | 1538-8514 |
| Popis: | A novel oral Hsp90 inhibitor, NVP-HSP990, has been developed and characterized in vitro and in vivo. In vitro, NVP-HSP990 exhibits single digit nanomolar IC50 values on three of the Hsp90 isoforms (Hsp90α, Hsp90β, and GRP94) and 320 nanomolar IC50 value on the fourth (TRAP-1), with selectivity against unrelated enzymes, receptors, and kinases. In c-Met amplified GTL-16 gastric tumor cells, NVP-HSP990 dissociated the Hsp90-p23 complex, depleted client protein c-Met, and induced Hsp70. NVP-HSP990 potently inhibited the growth of human cell lines and primary patient samples from a variety of tumor types. In vivo, NVP-HSP990 exhibits drug-like pharmaceutical and pharmacologic properties with high oral bioavailability. In the GTL-16 xenograft model, a single oral administration of 15 mg/kg of NVP-HSP990 induced sustained downregulation of c-Met and upregulation of Hsp70. In repeat dosing studies, NVP-HSP990 treatment resulted in tumor growth inhibition of GTL-16 and other human tumor xenograft models driven by well-defined oncogenic Hsp90 client proteins. On the basis of its pharmacologic profile and broad-spectrum antitumor activities, clinical trials have been initiated to evaluate NVP-HSP990 in advanced solid tumors. Mol Cancer Ther; 11(3); 730–9. ©2012 AACR. |
| Databáze: | OpenAIRE |
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