Abstract #5632: NVP-BEP800: an orally bioavailable small molecule Hsp90 inhibitor with potent in vivo antitumor activity

The ubiquitously expressed molecular chaperone Heat Shock Protein 90 (HSP90) has attracted substantial interest as a therapeutic target for anticancer drugs since HSP90 ATPase inhibition induces simultaneous degradation of multiple oncogenic \#8220;client\#8221; proteins. The most advanced HSP90 inhibitors are of the benzoquinone ansamycin class which have shown promising activity in human tumor xenograft models. In addition to the natural compound derived inhibitors a number of synthetic HSP90 inhibitors, such as NVP-AUY922, are now in clinical trials. The ansamycin class of inhibitors and NVP-AUY922 are administered intravenously. We have developed a novel synthetic HSP90 inhibitor which can be formulated for intravenous administration but also has good oral bioavailability in mice and rats. The acute tolerated dose (ATD) of an adipate salt of NVP-BEP800 in nude mice is >250 mg/kg whereas the maximum tolerated dose (MTD) when administered orally once per day is 40 mg/kg. The human breast cancer cell line BT-474 was used as the main model to evaluate the pharmacokinetic profile and efficacy of NVP-BEP800. BT-474 cells express estrogen receptors and high levels of ErbB2 both of which are Hsp90 client proteins. The pharmacokinetic profile of NVP-BEP800 in mice was evaluated in BT-474 tumor bearing nude mice. Oral dosing of 30 mg/kg to BT474 tumour bearing animals achieved a tumour C_max 350-fold greater than the cellular GI₅₀ with significant amounts retained in the tumour for 24 hours. These results were confirmed by quantitative whole body autoradiography using ¹⁴C-BEP800. Decreased levels of ErbB2 and increased levels of HSP70 - hallmarks of HSP90 inhibition - were observed after single dose administration. A significant effect on these pharmacodynamic markers was observed from 3-6 hours after dosing and lasted about 24 hours. The pharmacokinetic and pharmacodynamic data supported that NVP-BEP800 could be administered in a daily schedule at 30 mg/kg. Significant tumour regression was observed following daily oral dosing of 30 mg/kg without significant changes in body weight. Additional studies with different dosing intervals showed that once weekly dosing also exhibited significant tumour growth inhibition demonstrating a potential for dosing regimen flexibility with this compound. NVP-BEP800 was also highly efficacious against B-Raf mutant A375 melanoma and ErbB2/ER negative rat BN472 breast cancer xenografts. Overall, we demonstrate that NVP-BEP800 is a potent, novel Hsp90 inhibitor with good oral pharmacokinetic properties and exhibits potent anti-tumour effects with concurrent effects on client proteins following either once daily or weekly administration to nude mice bearing human tumour xenografts.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5632.