Abstract
Abstract Hsp90 is recognized as a potential target for the treatment of cancer, due to its chaperone functions that are required for maintaining the stability and/or active conformation of signalling molecules essential for tumorigenesis. The development of small molecule Hsp90 inhibitors has become an extremely competitive field of research. Here for the first time we present biological and pharmacological properties of NVP-HSP990, a potent oral Hsp90 inhibitor discovered by Novartis. In vitro, NVP-HSP990 potently inhibits all 4 isoforms of Hsp90 (Hsp90α, Hsp90β, TRAP-1 and GRP94) and has no major activities in a safety pharmacology panel of kinases, receptors and enzymes evaluated. NVP-HSP990 demonstrates broad-spectrum anti-tumor activities in tumor cell lines (IC 50s ranging from 4-35 nM) and primary patient samples (mean IC50 =49 nM). In vivo, NVP-HSP990 is highly bioavailable across species and a single oral administration of 15 mg/kg induces sustained target inhibition up to 7 days as indicated by downregulation of client protein (c-Met) and upregulation of Hsp70 in a cMet overexpressing gastric GTL16 xenograft tumor model. Weekly administration of NVP-HSP990 was efficacious in a broad range of mouse and rat human tumor xenograft models driven by well defined oncogenic Hsp90 client proteins. In summary, NVP-HSP990 represents a novel class of oral Hsp90 inhibitors with unique and superior pharmacological and drug-like properties. NVP-HSP990 is currently being evaluated in Phase I clinical trial in advanced solid tumors. In addition, we will present multiple secreted biomarkers for Hsp90 that were identified through a novel in-silico data mining approach. Several of these biomarkers have been validated both in vitro and in vivo, and have the potential to be utilized as clinical pharmaco-dynamic markers in the development of Hsp90 inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2605. doi:10.1158/1538-7445.AM2011-2605
Published Version
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