Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014 Sep;6(14):1587-605.
doi: 10.4155/fmc.14.89.

Alternative approaches to Hsp90 modulation for the treatment of cancer

Jessica A Hall  1 , Leah K Forsberg, Brian S J Blagg
Affiliations

Alternative approaches to Hsp90 modulation for the treatment of cancer

Jessica A Hall et al. Future Med Chem. 2014 Sep.

Abstract

Hsp90 is responsible for the conformational maturation of newly synthesized polypeptides (client proteins) and the re-maturation of denatured proteins via the Hsp90 chaperone cycle. Inhibition of the Hsp90 N-terminus has emerged as a clinically relevant strategy for anticancer chemotherapeutics due to the involvement of clients in a variety of oncogenic pathways. Several immunophilins, co-chaperones and partner proteins are also necessary for Hsp90 chaperoning activity. Alternative strategies to inhibit Hsp90 function include disruption of the C-terminal dimerization domain and the Hsp90 heteroprotein complex. C-terminal inhibitors and Hsp90 co-chaperone disruptors prevent cancer cell proliferation similar to N-terminal inhibitors and destabilize client proteins without induction of heat shock proteins. Herein, current Hsp90 inhibitors, the chaperone cycle, and regulation of this cycle will be discussed.

PubMed Disclaimer

Figures

Figure 1
Figure 1. The Hsp90 chaperone cycle
The two closed conformations of Hsp90 are highlighted in the figure. The first closed conformation is stabilized by Aha1. p23 then displaces Aha1, to form the second closed conformation.
Figure 2
Figure 2
Celastrol and gedunin.
Figure 3
Figure 3
Allosteric modulators of the Hsp90 chaperone cycle.
Figure 4
Figure 4. N-terminal inhibitors of Hsp90
(A) Geldanamycin and derivatives, (B) radicicol and derivatives, as well as (C) Pu-3 and purine-containing analogs.
Figure 5
Figure 5. Isoform selective inhibitors of Hsp90
Structures of (A) Hsp90α/β inhibitor, (B) resorcinol-containing Grp94 inhibitor and (C) purine-containing Grp94 inhibitor.
Figure 6
Figure 6. Effect of nucleotide binding to N-terminus on C-terminal dimerization
The percentages under each Hsp90 dimer reflect the likelihood of the C-terminus being either opened or closed.
Figure 7
Figure 7
C-terminal inhibitors of Hsp90.
See this image and copyright information in PMC

References

    1. Pratt WB. The role of heat shock proteins in regulating the function, folding, and trafficking of the glucocorticoid receptor. J Biol Chem. 1993;268(29):21455–21458. - PubMed
    1. Csermely P, Schnaider T, SoTi C, Prohászka Z, Nardai G. The 90-kDa molecular chaperone family: structure, function, and clinical applications. A comprehensive review. Pharmacol Ther. 1998;79(2):129–168. - PubMed
    1. Taipale M, Jarosz DF, Lindquist S. HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nat Rev Mol Cell Biol. 2010;11(7):515–528. - PubMed
    1. Li J, Soroka J, Buchner J. The Hsp90 chaperone machinery: conformational dynamics and regulation by co-chaperones. Biochim Biophys Acta. 2012;1823(3):624–635. - PubMed
    1. Li J, Buchner J. Structure, function and regulation of the Hsp90 machinery. Biomed J. 2013;36(3):106–117. - PubMed

Publication types

MeSH terms