Compound DescriptionNon-geldanamycin derivative Hsp90 inhibitor
Areas of ResearchBreast cancer, non–small cell lung cancer (NSCLC), and other solid tumors
Proposed Mechanism of ActionHsp90 is a ubiquitously expressed chaperone protein which is a critical regulator of the proper folding and conformation of many oncogenic client proteins, including human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), epidermal growth factor receptor (EGFR), AKT, c-KIT, B-Raf, and enchinoderm microtubule associated protein like 4-anaplastic lymphoma kinase (EML4-ALK).1,2 AUY922 inhibits the Hsp90 protein complex.1,2 This results in potential degradation of client proteins involved in oncogenesis, pro-survival signaling, and anti-apoptosis.1,2
Key Preclinical DataIn in vivo and in vitro preclinical studies, AUY922 binds to Hsp90 with high affinity in cancer cell lines of different tumor types. It destabilizes Hsp90 chaperoning complex and induces degradation of Hsp90 client proteins. This then results in induction of Hsp70, a sensitive pharmacodynamic marker of Hsp90 complex disruption.3,4
Clinical StatusThe first-in-human phase I/II dose escalation study evaluating AUY922 is complete, and the maximum tolerated dose (MTD) was determined.1 Four phase II studies are ongoing to determine the clinical benefits of AUY922 in patients with NSCLC. One of these studies is evaluating the efficacy of AUY922 compared to that of pemetrexed or docetaxel in patients with EGFR mutations who have progressed on prior EGFR TKI treatment.5 Other ongoing NSCLC studies are exploring AUY922 in patients who have received at least two lines of chemotherapy,6 in patients with "acquired resistance" to EGFR TKIs,7 and in patients with ALK-rearranged advanced NSCLC who have acquired resistance to prior ALK TKI therapy.8
The information contained herein was last updated on April 12, 2013.
All Compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.
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