AT13387, an inihibitor of HSP90 with options for oral delivery, is currently being administered as an intravenous formulation in a Phase II trial for patients with gastrointestinal stromal tumor (GIST cancer) in combination with imatinib, and also in a Phase I study in cancer patients with solid tumors.
Definition from NCI Drug Directory: A synthetic, orally bioavailable, small-molecule inhibitor of heat shock protein 90 (Hsp90) with potential antineoplastic activity. Hsp90 inhibitor AT13387 selectively binds to Hsp90, thereby inhibiting its chaperone function and promoting the degradation of oncogenic signaling proteins involved in tumor cell proliferation and survival. Hsp90, a chaperone protein upregulated in a variety of tumor cells, regulates the folding, stability and degradation of many oncogenic signaling proteins
Mode of Action: AT13387 is a selective small molecule inhibitor of Heat Shock Protein 90 (Hsp90).
Manufacturer: Astex Therapeutics www.astex-therapeutics.com/
Information at manufacturer site: http://astx.com/pipeline/products/clinical#at13387
Current Clinical Trials:
NCT01294202 A Study to Investigate the Safety and Efficacy of AT13387, Alone or in Combination With Imatinib, in Patients With GIST (Phase II) recruiting
The HSP90 inhibitor, AT13387, demonstrates potent anti-tumor activity in both imatinib-sensitive and imatinib-resistant gastrointestinal stromal tumor models.
Smyth et al poster number A217 presented in November 2011 at AACR/NCI/EORTC conference on Molecular Targets and Cancer Therapeutics.
Here is a quote from the abstract: "In vivo, the efficacy of AT13387 was tested in imatinib-sensitive (GIST-PSW) and imatinib-resistant (GIST430) xenograft models. AT13387, dosed once a week, inhibited the growth of both xenografts; depletion of phospho-KIT and inhibition of KIT signalling were again seen in these tumors. As expected, treatment with imatinib caused significant regression of the GIST-PSW tumors but not of GIST430. The combination of imatinib and AT13387 significantly enhanced tumor growth inhibition (T/C 21%) over either of the monotherapies (T/C 30% for AT13387, 46% for imatinib) in the GIST430 xenograft. Importantly, the combination was well tolerated."
Earlier, preclinical data showing efficacy for AT13387 in tumor models was presented at the American Association for Cancer Research annual meeting in April 2007. The effects of AT13387 have been investigated in several model systems including lung and melanoma models that have proved to be particularly sensitive to the agent.
Astex Therapeutics presented key data differentiating its HSP90 inhibitor, AT13387, at the 100th AACR Annual Meeting 2009. This highlighted the significance of the extremely long duration of the tumor-targeted pharmacodynamic action of AT13387.
Presentation Title: Significance of long term pharmacodynamic actions of the HSP90 inhibitor AT13387
This can be seen at:
“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. Studies in tumor 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.”