NVP-AUY922: A novel small molecule HSP90 inhibitor with potent in vivo antitumor efficacy

B279

Heat Shock Protein 90 (HSP90) is a ubiquitously expressed molecular chaperone with ATPase activity which plays an important role in the conformational maturation and activation of a large number of client proteins that have been implicated in oncogenesis. HSP90 has attracted considerable interest as a therapeutic target for anticancer drugs since HSP90 ATPase inhibition induces simultaneous degradation of multiple oncogenic proteins. The most advanced HSP90 inhibitors are of the benzoquinone ansamycin class which have shown promising activity in human tumor xenograft models. NVP-AUY922, is a novel synthetic resorcinylic isoxazole HSP90 inhibitor which recently entered Phase I clinical trials. In a competitive fluorescent polarization assay, NVP-AUY922 inhibited Hsp90β with an IC50 of 21nM and a Ki of 9nM. Inhibition of HSP90 translates into anti-proliferative effect of human breast cancer tumor cells with GI50 values in the range of 3-10 nM. Importantly, treatment of cell lines with NVP-AUY922 consistently induced dissociation of p23/Hsp90, HSP72 upregulation and client protein depletion - hallmarks of HSP90 inhibition. Intravenous administration of NVP-AUY922 to athymic mice (25 mg/kg) resulted in drug levels exceeding 1000-fold cellular GI50 for about 2 days in BT-474 breast cancer xenografts. Tumor stasis was observed when the compound was administered once per week and was accompanied by apoptosis. Therapeutic effects were also concordant with changes in pharmacodynamic markers including p23/Hsp90 dissociation, decreases in ERBB2 and P-AKT as well as increased HSP72. Overall, we demonstrate that NVP-AUY922 is a potent, novel HSP90 inhibitor with long lasting tumor retention and rapid organ clearance. This translates into potent anti-tumor effect with concurrent effects on client proteins when administered once weekly to nude mice bearing human breast cancer xenograft tumors.