THE NOVEL ORAL HSP90 INHIBITOR NVP-HSP990 EXHIBITS POTENT AND BROAD-SPECTRUM ANTI-TUMOR ACTIVITIES IN VITRO AND IN VIVO
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Gao, Zhenhai, Menezes, Daniel, Machajewski, Timothy, Abrams, Tinya, Jensen, Michael Rugaard, Yu, Guoying, Stuart, Darrin, Duhl, David, Pryer, Nancy and Sellers, William (2012) THE NOVEL ORAL HSP90 INHIBITOR NVP-HSP990 EXHIBITS POTENT AND BROAD-SPECTRUM ANTI-TUMOR ACTIVITIES IN VITRO AND IN VIVO. Molecular Cancer Therapeutics. ISSN 1535-7163
Abstract
A novel oral Hsp90 inhibitor, NVP-HSP990, has been developed and characterized in vitro and in vivo. In vitro, NVP-HSP990 exhibits single digit nM IC50 values on three of the Hsp90 isoforms (Hsp90α, Hsp90β, and GRP94) and 320 nM IC50 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 pharmacological 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 pharmacological profile and broad spectrum anti-tumor activities, clinical trials have been initiated to evaluate NVP-HSP990 in advanced solid tumors.
| Item Type: | Article |
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| Additional Information: | author can archive post-print (ie final draft post-refereeing); Authors final version may be deposited on institutional website/ repository if required by institution |
| Keywords: | NVP-HSP990, HSP90 inhibitor, pharmacology, PK-PD, efficacy |
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| Date Deposited: | 13 Oct 2015 13:15 |
| Last Modified: | 13 Oct 2015 13:15 |
| URI: | https://oak.novartis.com/id/eprint/5430 |