Research article

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

Michael Rugaard Jensen¹ , Joseph Schoepfer¹ , Thomas Radimerski¹ , Andrew Massey² , Chantale T Guy³ , Josef Brueggen¹ , Cornelia Quadt⁴ , Alan Buckler³ , Robert Cozens¹ , Martin J Drysdale² , Carlos Garcia-Echeverria¹ and Patrick Chène¹

¹Novartis Institutes for BioMedical Research, Oncology Research, Klybeckstrasse 141, CH-4057 Basel, Switzerland

²Vernalis Ltd, Granta Park, Great Abington, Cambridge, CB1 6GB, UK

³Novartis Institutes for BioMedical Research, 500 Technology Square, Cambridge, MA 02139, USA

⁴Novartis Pharma AG, Forum 1, Novartis Campus, CH-4056 Basel, Switzerland

author email corresponding author email

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

Published:	22 April 2008

Abstract

Introduction

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

Methods

The concentrations of the HSP90 inhibitor NVP-AUY922 required to reduce cell numbers by 50% (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 xenograft 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 cell lines with GI₅₀ values in the range of 3 to 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 in excess of 1,000 times the cellular GI₅₀ value for about 2 days. Significant growth inhibition and good tolerability were observed when the compound was administered once per week. Therapeutic effects were concordant with changes in pharmacodynamic markers, including HSP90-p23 dissociation, decreases in ERBB2 and P-AKT, and increased HSP70 protein levels.

Conclusion

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 recently has entered clinical phase I breast cancer trials.