Hsp90 inhibitor

Hsp90 inhibitor
Drug class
Geldanamycin, the first discovered Hsp90 inhibitor.
Class identifiers
Use	Antineoplastic
Biological target	Hsp90

An Hsp90 inhibitor is a substance that inhibits that activity of the Hsp90 heat shock protein. Since Hsp90 stabilizes a variety of proteins required for survival of cancer cells, these substances may have therapeutic benefit in the treatment of various types of malignancies. Furthermore, a number of Hsp90 inhibitors are currently undergoing clinical trials for a variety of cancers. Hsp90 inhibitors include the natural products geldanamycin and radicicol as well as semisynthetic derivatives 17-N-Allylamino-17-demethoxygeldanamycin (17AAG).

Among heat shock proteins the focus on HSP90 has increased due to its involvement in several cellular phenomenon and more importantly in disease progression. HSP90 keeps the death proteins in an apoptosis resistant state by direct association. Its wide range of functions results from the ability of HSP90 to chaperone several client proteins that play a central pathogenic role in human diseases including cancer, neurodegenerative diseases and viral infection.Geldanamycin directly binds to the ATP-binding pocket in the N-terminal domain of Hsp90 and, hence, blocks the binding of nucleotides to Hsp90. Analysis of the effects of Geldanamycin on steroid receptor activation indicates that the antibiotic blocks the chaperone cycle at the intermediate complex, preventing the release of the receptor from Hsp90 and, eventually, resulting in its degradation.Ewing’s sarcoma shows several deregulated loops mediating cell survival and proliferation. So their blockade is a promising therapeutic approach. Proteosome analysis revealed that Hsp90 is differentially expressed between ewing’s sarcoma cell lines, sensitive and resistant to specific IGF1R/KIT inhibitors. The in vitro IGF1R/KIT pathway blockade on ewing’s sarcoma cell lines and classified ewing’s sarcoma cell lines as resistant and sensitive to blockade of pathway. Inhibition of Hsp90 with 17AAG and siRNA resulted in reduction of cell lines growth and survival. The inhibition of Hsp90 causes the proteosomal destruction of client proteins- Akt, KIT and IGF1R. This effect could be due to precluding physical contact between client proteins and Hsp90. So since the molecular chaperones are overexpressed in a wide variety of cancer cells and in virally transformed cells, inhibiting the function of these chaperones is essential to controlling cancer cells, as this would affect the activity of signaling proteins. The availability of drugs that can specifically target Hsp90 and inhibit its function, resulting in the depletion of client proteins, has made Hsp90 a novel and exciting target for cancer therapy.