Old and New Approaches to Target the Hsp90 Chaperone

(E-pub Ahead of Print)

Author(s): Jackee Sanchez, Trever R. Carter, Mark S. Cohen*, Brian S. Blagg.

Journal Name: Current Cancer Drug Targets

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Abstract:

The 90-kDa heat shock protein (Hsp90) is a molecular chaperone which ensures cellular proteostasis by maintaining the folding, stabilization, activation, and degradation of over 400 client proteins. Hsp90 is not only critical for routine protein maintenance in healthy cells, but also during states of cellular stress, such as cancer and neurodegenerative diseases. Due to its ability to effect phosphorylation of numerous client proteins, inhibition of Hsp90 has been an attractive anticancer approach since the early 1990’s, when researchers identified a druggable target on the amino terminus of Hsp90 for a variety of cancers. Since then, 17 Hsp90 inhibitors that target the chaperone’s N-terminal domain, have entered clinical trials. None, however, have been approved thus far by the FDA as a cancer monotherapy. In these trials, a major limitation observed with Hsp90 inhibition at the N-terminal domain was dose-limiting toxicities and relatively poor pharmacokinetic profiles. Despite this, preclinical and clinical research continues to show that Hsp90 inhibitors effectively target cancer cell death and decrease tumor progression supporting the rationale for development of novel Hsp90 inhibitors. Here, we present an in-depth overview of the Hsp90 inhibitors used in clinical trials. Finally, we present current shifts in the field related to targeting the carboxy-terminal domain of Hsp90 as well as to development of isoform-selective inhibitors as a means to bypass the pitfalls of current Hsp90 inhibitors and improve clinical trial outcomes.

Keywords: Cancer, Chaperones, Geldanamycin, Grp94, Hsp90, Novobiocin, TAS-116, TRAP1

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(E-pub Ahead of Print)
DOI: 10.2174/1568009619666191202101330
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