The Novel Oral Hsp90 Inhibitor Exhibits Potent and Braod-Spectrum Anti-Tumor Activities In Vitro and In Vivo
Menée in vitro et in vivo à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un nouvel inhibiteur de la protéine de choc thermique 90, un composé par voie orale appelé NVP-HSP990
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.
http://mct.aacrjournals.org/content/early/2012/01/12/1535-7163.MCT-11-0667.abstract