The novel oral Hsp90 inhibitor NVP-HSP990 exhibits potent and broad-spectrum antitumor activities in vitro and in vivo.
A novel oral inhibitor， NVP-HSP990， has been developed and characterized in vitro and in vivo. In vitro， NVP-HSP990 exhibits single digit nanomolar IC(50) values on three of the isoforms (α， β， and ) and 320 nanomolar IC(50) value on the fourth ()， with selectivity against unrelated enzymes， receptors， and kinases. In amplified GTL-16 gastric cells， NVP-HSP990 dissociated the -complex， depleted client protein ， and induced . NVP-HSP990 potently inhibited the growth of cell lines and primary patient samples from a variety of 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 and upregulation of . In repeat dosing studies， NVP-HSP990 treatment resulted in inhibition of GTL-16 and other driven by well-defined oncogenic 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 .