The Heat Shock Protein 90 Chaperone Complex: An Evolving Therapeutic Target
M. F. Barginear,
C. Van Poznak,
C. A. Hudis,
D. R. Budman.
Hsp90 (heat shock protein 90) is a molecular chaperone that modulates the stability and/or transport of a diverse set of critical cellular regulatory, metabolism, organization, and signaling proteins. Binding to Hsp90 is required for normal function of many proteins. In addition, Hsp90 has an extra-cellular function. It is found in two isotypes: α which is inducible and β which is constitutive. Tumor cells frequently over express Hsp90α, and Hsp90 is implicated in cancer progression. Hence Hsp90 has emerged as a potential target for cancer treatment. A variety of agents have been found to interfere with Hsp function, mainly by binding to an ATP binding site on the molecule. More recent agents interfere with protein binding or the dimerization of Hsp90 needed for function. Preclinical studies have demonstrated that disruption of the many client proteins chaperoned by Hsp90 is achievable and associated with significant growth inhibition, both in vitro and in tumor xenografts. As a result, agents which interfere with this proteins function are being tested in the clinic as a targeted method of interfering with malignant growth. We review the current clinical status of therapeutic efforts to perturb this pathway and discuss future directions.
Keywords: HSP90, inhibitor, signal transduction, clinical trials
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