Cambridge, UK, 14th April 2009. Astex Therapeutics announced today that key data differentiating its HSP90 inhibitor, AT13387, from other compounds in this class, will be presented at the 100th American Association for Cancer Research (AACR) Annual Meeting 2009, to be held April 18-22, 2009, at the Colorado Convention Center in Denver, Colorado.
AT13387 was discovered using the Company’s leading fragment-based drug discovery platform, Pyramid™. The compound is a selective small molecule inhibitor of Heat Shock Protein 90 (HSP90) to treat cancer and is the third drug candidate from Astex’s internal discovery and development programmes to be approved for clinical trials.
Preclinical data showing the efficacy of AT13387 in tumour models was previously presented at the AACR Annual Meeting in April 2007 and Astex commenced the first Phase I clinical trial of the compound in cancer patients during 2008. Data reported at this meeting will highlight the significance of the extremely long duration of the tumour-targeted pharmacodynamic action of AT13387. Studies in tumour models in vivo show that a single dose of AT13387 results in loss of client proteins for 72 hrs or more, substantially longer than reported for other inhibitors in this class. Newly presented in vitro data reveal how this property provides a means to clearly differentiate the superior profile of AT13387 from other drugs in this class The significance of these observations to the ongoing Phase I clinical study with AT13387 are under investigation.
Abstract
Heat Shock Protein 90 (HSP90) is a member of a family of molecular chaperone proteins which directs the folding of polypeptides into functional configurations affecting stabilisation and activation. Many of these proteins are oncogenes regulating tumour cell growth, survival and apoptosis. Inhibition of HSP90 with AT13387, a small molecule inhibitor discovered using fragment-based drug discovery, has been shown to result in client protein degradation, suppression of cytoplasmic signalling, cell cycle arrest and apoptosis. Some of these pharmacodynamic actions can last as long as 3 days in tumor xenografts in mice following treatment with a single dose of AT13387. The kinetics of the direct effects on client protein levels were investigated and compared to the kinetics of the biochemical and functional consequences of client protein loss (e.g. HSP70 induction, Akt pathway status, PARP cleavage) to understand the significance of these different events.
Results: AT13387 has potent anti-proliferative effects in vitro in a panel of cell lines including A375, SK-MEL-28 melanoma cells, NCI-H1975 NSCLC cells, SKBr3 breast adenocarcinoma and SKOV3 ovarian adenocarcinoma cells. Pharmacodynamic studies in vivo in xenografts established from the mutant BRAF melanoma cell line A375, show a single dose of AT13387 resulted in loss of the client proteins Akt and BRAF which was apparent by 6hr but continued for ~72 hrs or more. An increase in HSP70 protein levels and a concomitant increase in cleaved PARP protein levels was observed over the 6 - 72hr period. The earliest effect observed however, was a reduction in phospho-Akt(Ser473) and phospho-S6 (Ser240/244) levels by 3h following treatment. This indicates that the effect of HSP90 inhibition on phosphorylation of key proteins in the Akt pathway is not simply a consequence of destabilisation of Akt and loss of Akt protein but likely also includes either an action upstream of Akt or destabilization of a complex supported by HSP90 and including Akt activating kinases. The significance of these observations to the ongoing Phase I clinical study with AT13387 are under investigation.
About Astex Therapeutics
Astex is a UK-based biotechnology company that discovers and develops novel small molecule therapeutics. Using its pioneering fragment-based drug discovery platform Pyramid™, Astex has built a pipeline of five molecularly-targeted oncology drugs, of which three are currently being tested in clinical trials and two are in pre-clinical development. In addition to its proprietary research programmes, Astex’s productivity in lead discovery has been endorsed through numerous partnerships with major pharmaceutical companies, including AstraZeneca, Bayer-Schering, Boehringer Ingelheim, Novartis and Johnson & Johnson.
For further information on Astex please visit the Company’s website at www.astex-therapeutics.com
