Spotlight on 17-AAG as an Hsp90 inhibitor for molecular targeted cancer treatment.

Hsp90 is a ubiquitous chaperone with important roles in the organization and maturation of client proteins that are involved in the progression and survival of cancer cells. Multiple oncogenic pathways can be affected by inhibition of Hsp90 function through degradation of its client proteins. That makes Hsp90 a therapeutic target for cancer treatment. 17-allylamino-17-demethoxy-geldanamycin (17-AAG) is a potent Hsp90 inhibitor that binds to Hsp90 and inhibits its chaperoning function, which results in the degradation of Hsp90's client proteins. There have been several preclinical studies of 17-AAG as a single agent or in combination with other anticancer agents for a wide range of human cancers. Data from various phases of clinical trials show that 17-AAG can be given safely at biologically active dosages with mild toxicity. Even though 17-AAG has suitable pharmacological potency, its low water solubility and high hepatotoxicity could significantly restrict its clinical use. Nanomaterials-based drug delivery carriers may overcome these drawbacks. In this paper, we review preclinical and clinical research on 17-AAG as a single agent and in combination with other anticancer agents. In addition, we highlight the potential of using nanocarriers and nanocombination therapy to improve therapeutic effects of 17-AAG.

Talaei S ，Mellatyar H ，Asadi A ，Akbarzadeh A ，Sheervalilou R ，Zarghami N ... -  《-》

Drug-mediated targeted disruption of multiple protein activities through functional inhibition of the Hsp90 chaperone complex.

Stravopodis DJ ，Margaritis LH ，Voutsinas GE 《CURRENT MEDICINAL CHEMISTRY》

Targeted cancer therapy through 17-DMAG as an Hsp90 inhibitor: Overview and current state of the art.

Heat shock protein 90 (Hsp90) is an evolutionary preserved molecular chaperone which mediates many cellular processes such as cell transformation, proliferation, and survival in normal and stress conditions. Hsp90 plays an important role in folding, maturation, stabilization and activation of Hsp90 client proteins which all contribute to the development, and proliferation of cancer as well as other inflammatory diseases. Functional inhibition of Hsp90 can have a massive effect on various oncogenic and inflammatory pathways, and will result in the degradation of their client proteins. This turns it into an interesting target in the treatment of different malignancies. 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) as a semi-synthetic derivative of geldanamycin, has several advantages over 17-Allylamino-17-demethoxygeldanamycin (17-AAG) such as higher water solubility, good bioavailability, reduced metabolism, and greater anti-tumour capability. 17-DMAG binds to the Hsp90, and inhibits its function which eventually results in the degradation of Hsp90 client proteins. Here, we reviewed the pre-clinical data and clinical trial data on 17-DMAG as a single agent, in combination with other agents and loaded on nanomaterials in various cancers and inflammatory diseases.

Mellatyar H ，Talaei S ，Pilehvar-Soltanahmadi Y ，Barzegar A ，Akbarzadeh A ，Shahabi A ，Barekati-Mowahed M ，Zarghami N ... -  《-》

Alleviating neurodegeneration by an anticancer agent: an Hsp90 inhibitor (17-AAG).

Waza M ，Adachi H ，Katsuno M ，Minamiyama M ，Tanaka F ，Sobue G ... -  《-》

Discovery and development of heat shock protein 90 inhibitors as anticancer agents: a review of patented potent geldanamycin derivatives.

Kim T ，Keum G ，Pae AN 《-》