17 AAG for HSP90 inhibition in cancer--from bench to bedside.
Heat shock protein 90 (HSP90) family of proteins are ubiquitous molecular chaperones that are involved in folding, activation, maturation and assembly of many proteins that include essential mediators of signal transduction and cell cycle progression. They are abundant in eukaryotic cells and localized to the cytoplasm, mitochondria as well as the endoplasmic reticulum under normal conditions, making up 1-2% of all cellular proteins. HSP90 proteins have increased expression in a number of malignancies. A large number of HSP90 client proteins have been shown to be necessary for the development, proliferation and survival of specific types of cancers. HSP90 inhibition can affect multiple oncogenic pathways and involved proteins, therefore make it an attractive target for drug development. This article serves as an overview of the pre-clinical data and clinical trial data on HSP90 inhibitor 17-AAG in different malignancies. 17-AAG has shown significant anti-tumor activity against a spectrum of cancers in the pre-clinical studies and information from various phases of clinical trials is growing. The potential indication of 17-AGG for the treatment of refractory multiple myeloma now awaits for the results of two phase III studies. More work needs to be done before the broader oncological use of HSP90 inhibitors in the area of defining HSP90 client proteins, understanding the mechanism of HSP90 actions, identifying reliable surrogate markers for HSP90 inhibition in vivo and optimizing drug delivery and efficacy.
Usmani
Saad Z
SZ
Division of Hematology-Oncology, Lea Foundation's Center for Hematologic Disorders, Carole & Ray Neag Comprehensive Cancer Center, University of Connecticut Health Center, Farmington, CT, USA.
Bona
Robert
R
Li
Zihai
Z
D016227:Benzoquinones / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014839:Vomiting / Q000139:chemically induced
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin