Melanoma Molecular Maps Projects



Title: List of HSP90 inhibitors
Legend: Heat shock protein 90 (HSP90) is an ubiquitous, highly expressed molecular chaperone protein capable of sensing cellular stress. It functions as a multiprotein chaperone complex with co-chaperones that include HSP70, HSP40, and HOP. Upon ATP binding and hydrolysis, this intermediate complex forms a mature chaperone complex containing p23, which catalyzes the conformational maturation of "client protein" substrates. Multiple client proteins of the Hsp90 chaperone complex are involved in signal-transduction pathways, cell-cycle regulation, and apoptosis pathways commonly deregulated in cancer. Although essential for cellular viability, the pharmacological inhibition of this chaperone has emerged as an attractive approach for inhibition of tumorigenesis. The natural product geldanamycin, a benzoquinone ansamycin, binds to HSP90 (ATP binding pocket), inhibits its ATPase activity, and decreases cellular levels of client proteins involved in cancer cell survival, such as mutated p53, mutated BRAF, AKT, Bcr-Abl, and ErbB2. Several HSP90 inhibitors have therefore been developed, such as 17-AAG (tanespimycin) and 17-DMAG (two geldanamycin derivatives), KW-2478, IPI-504, SNX-5422, CNF-1010, DMAG-N-oxide, VER-49009 (CCT129397), VER-50589, radicicol, CCT018159 (VER-00063579), and STA-9090. They have shown potent antiproliferative activity in many malignant cell lines in vitro and inhibit tumor growth in mouse xenograft models. Some of them have reached the clinical phase of experimentation. REFERENCES: [1] Powers MV et al, Endocrine-Related Cancer 2006, 13: S125-S135; [2] Bishop SC et al, Curr Cancer Drug Targets 2007, 7:369-88. [3] Xu W et al, Clin Cancer Res 2007, 13:1625-9
Author: The MMMP Team (updated: Dec 2007)

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