Title:Old and New Approaches to Target the Hsp90 Chaperone
Volume: 20
Issue: 4
Author(s): Jackee Sanchez, Trever R. Carter, Mark S. Cohen*Brian S.J. Blagg
Affiliation:
- Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109,United States
Keywords:
Cancer, chaperones, geldanamycin, Grp94, Hsp90, novobiocin, TAS-116, TRAP1.
Abstract: The 90-kDa heat shock protein (Hsp90) is a molecular chaperone that 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 affect
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 Nterminal
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 the 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 the development of isoform-selective inhibitors as a means to bypass the
pitfalls of current Hsp90 inhibitors and improve clinical trial outcomes.
