NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models

Michael R Jensen , Joseph Schoepfer , Thomas Radimerski , Andrew Massey , Chantale T Guy , Josef Brueggen , Cornelia Quadt , Alan Buckler , Robert Cozens , Martin J Drysdale , Carlos Garcia-Echeverria and Patrick Chene

Breast Cancer Research 2008, 10:R33doi:10.1186/bcr1996


Published:	22 April 2008

Abstract (provisional)

Introduction

Heat shock protein 90 (HSP90) is a key component of a multi-chaperone complex involved in the posttranslational folding of a large number of client proteins many of which play essential roles in tumorigenesis. HSP90 has in recent years emerged as a promising new target for anticancer therapies.

Methods

The concentrations of the HSP90 inhibitor NVP-AUY922 required to reduce cell numbers by 50 percent (GI50 values) were established in a panel of breast cancer cell lines and patient derived human breast tumors. To investigate the properties of the compound in vivo, the pharmacokinetic profile, antitumor effect and dose regimen were established in a BT-474 breast cancer xenografts model. The effect on HSP90/p23 complexes, client protein degradation and heat shock response was investigated in cell culture and breast cancer xenografts by immunohistochemistry, Western blot analysis and immunoprecipitation.

Results

We show that the novel small molecule HSP90 inhibitor NVP-AUY922 potently inhibits the proliferation of human breast cancer tumor cell lines with GI50 values in the range of 3-126 nM. NVP-AUY922 induced proliferative inhibition concurrent with HSP70 upregulation and client protein depletion - hallmarks of HSP90 inhibition. Intravenous acute administration of NVP-AUY922 to athymic mice (30 mg/kg) bearing subcutaneous BT-474 breast tumors resulted in drug levels exceeding 1,000-fold cellular GI50 for about 2 days. Significant growth inhibition and good tolerability was observed when the compound was administered once per week. Therapeutic effects were concordant with changes in pharmacodynamic markers including p23/HSP90 dissociation, decreases in ERBB2 and P-AKT as well as increased HSP70 protein levels.

Conclusions

NVP-AUY922 is a potent small molecule HSP90 inhibitor showing significant activity against breast cancer cells in cellular and in vivo settings. On the basis of its mechanism of action, preclinical activity profile, tolerability and pharmaceutical properties, the compound has recently entered clinical Phase I breast cancer trials.