One promising therapeutic strategy for treating cancer is to specifically target
signal transduction pathways that have a key role in oncogenic transformation and
malignant progression. Hsp90 is an emerging therapeutic target of interest for the
treatment of cancer. It is responsible for modulating cellular response to stress by
maintaining the function of numerous signaling proteins - known as ‘client proteins’ -
that are associated with cancer cell survival and proliferation. Many cancers result from
specific mutations in, or aberrant expression of, these client proteins. Small molecule
Hsp90 inhibitors bind to the ATP binding pocket, inhibit chaperone function and could
potentially result in cytostasis or cell death. Consequently, many client proteins are
targeted for degradation via the ubiquitin-proteasome pathway including receptor and
non receptor kinases (Erb-B2, epidermal growth factor receptor, and Src family
kinases), serine/threonine kinases (c-Raf-1 and Cdk4), steroid hormone receptors
(androgen and estrogen), and apoptosis regulators such as mutant p53. Inhibition of
Hsp90 function Hsp90 has also proven effective in kiling cancer cells that have
developed resistance to targeted therapies such as kinase inhibitors.
This review is intended to update recent developments in new Hsp90 inhibitors as
antitumors agents, the design, biological evaluation and their clinical trials studies.
Keywords: Cancer, heat shock protein 90 (Hsp90), co-chaperone, client proteins,
antitumor agents, NTD-Hsp90 inhibitors, CTD-Hsp90 inhibitors, apoptosis,
proteasome.
