Recent advances in Hsp90 inhibitors as antitumor agents.
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 signalling 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 has also proven effective in killing 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.
Messaoudi
S
S
Univ. Paris-Sud, CNRS, Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, Châtenay-Malabry, F-92296, France. samir.messaoudi@u-psud.fr
Peyrat
J F
JF
Brion
J D
JD
Alami
M
M
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002986:Clinical Trials as Topic; D004354:Drug Screening Assays, Antitumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D000251:Adenosine Triphosphatases