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THE NOVEL ORAL HSP90 INHIBITOR NVP-HSP990 EXHIBITS POTENT AND BROAD-SPECTRUM ANTI-TUMOR ACTIVITIES IN VITRO AND IN VIVO

Gao, Zhenhai and Menezes, Daniel and Machajewski, Timothy and Abrams, Tinya and Jensen, Michael Rugaard and Yu, Guoying and Stuart, Darrin and Duhl, David and 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

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