Hsp90: A novel target for cancer therapy Journal Article

Authors: Solit, D. B.; Rosen, N.
Article Title: Hsp90: A novel target for cancer therapy
Abstract: Hsp90 is a molecular chaperone required for the stress-survival response, protein refolding, and the conformational maturation of a variety of signaling proteins. Natural products that bind selectively to Hsp90 and inhibit its function have been used to determine its biologic role. Experiments with these drugs have shown that Hsp90 is required for maintaining the malignant phenotype of cancer cells. Studies in vivo show that Hsp90 inhibitors have antitumor activity when given alone and in combination with cytotoxics. The basis for the therapeutic index (selective toxicity to cancer cells) of Hsp90 inhibitors is complex and may have to do with induction of degradation of mutant oncoproteins and other proteins necessary for their proliferation and survival as well as to an enhanced requirement of these cells for Hsp90 stress-survival functions. Based on these data, 17-AAG, an ansamycin antibiotic inhibitor of Hsp90, is being tested extensively in clinical trials in patients with advanced cancer. These trials demonstrate that the biologic function of Hsp90 can be inhibited in patients and antitumor activity has been noted in patients with breast cancer, multiple myeloma and other cancers. These data and the physicochemical properties of 17-AAG that limit its use as a drug, have led to broad efforts to develop improved and novel Hsp90 inhibitors. This article will review the preclinical data which supports the testing of HSP90 inhibitors as cancer drugs and update the reader on the current status of the ongoing clinical trials of Hsp90 inhibitors. © 2006 Bentham Science Publishers Ltd.
Keywords: unclassified drug; oncoprotein; fludarabine; clinical trial; review; cisplatin; cytotoxic agent; doxorubicin; advanced cancer; drug potentiation; nonhuman; solid tumor; unspecified side effect; antineoplastic agents; paclitaxel; combined modality therapy; cytarabine; rituximab; mutant protein; protein conformation; protein function; neoplasms; phenotype; animals; cell survival; complex formation; imatinib; unindexed drug; melanoma; bortezomib; ovary cancer; pharmacodynamics; breast cancer; protein degradation; epidermal growth factor receptor 2; 7 ethyl 10 hydroxycamptothecin; protein binding; in vivo study; antineoplastic activity; drug structure; chronic myeloid leukemia; drug design; structure-activity relationship; cancer therapy; docetaxel; irinotecan; hematologic malignancy; protein processing; cancer cell; energy transfer; vorinostat; heat shock protein 90 inhibitor; heat shock protein 90; hsp90 heat-shock proteins; stress; molecular structure; thyroid cancer; drug cytotoxicity; protein folding; kidney cancer; trastuzumab; natural product; multiple cancer; clinical trials; drug use; physical chemistry; 2 morpholino 8 phenylchromone; butyric acid; her2; mastocytosis; chaperone; midostaurin; ansamycin derivative; cnf 1010; 17 allylamino 17 demethoxygeldanamycin; 7 hydroxystaurosporine; cytotoxics; hormone-refractory prostate cancer; rb-negative tumors; 17 dimethylaminoeothylamino 17demethoxygeldanamycin
Journal Title: Current Topics in Medicinal Chemistry
Volume: 6
Issue: 11
ISSN: 1568-0266
Publisher: Bentham Science Publishers  
Date Published: 2006-06-01
Start Page: 1205
End Page: 1214
Language: English
DOI: 10.2174/156802606777812068
PUBMED: 16842157
PROVIDER: scopus
Notes: --- - "Cited By (since 1996): 86" - "Export Date: 4 June 2012" - "CODEN: CTMCC" - "Source: Scopus"
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MSK Authors
  1. Neal Rosen
    359 Rosen
  2. David Solit
    431 Solit