Preclinical Development The Novel Oral Hsp90 Inhibitor NVP-HSP990 Exhibits Potent and Broad-spectrum Antitumor Activities In Vitro and In Vivo

A novel oral Hsp90 inhibitor, NVP-HSP990, has been developed and characterized in vitro and in vivo. In vitro, NVP-HSP990 exhibits single digit nanomolar IC50 values on three of the Hsp90 isoforms (Hsp90a, Hsp90b, and GRP94) and 320 nanomolar IC50 value 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 pharmacologic properties with high oral bioavailability. In the GTL-16 xenograftmodel, a single oral administration of 15mg/kg ofNVP-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 pharmacologic profile and broad-spectrum antitumor activities, clinical trials have been initiated to evaluate NVP-HSP990 in advanced solid tumors. Mol Cancer Ther; 11(3);