Current Cancer Drug Targets

Ruiwen Zhang 
Texas Tech University Health Sciences Center
1300 Coulter Drive
Amarillo, TX 79106
USA

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Natural Product Origins of Hsp90 Inhibitors

Author(s): Yoshimasa Uehara.

Abstract:

The currently used Hsp90 inhibitors, geldanamycin, herbimycin A and radicicol, were isolated many years ago from Streptomyces and fungi originally for their antiprotozoal activity, herbicidal activity and antifungal activity, respectively. In the mid 1980s, it was found that the benzoquinone ansamycin antibiotics (herbimycin A, geldanamycin, and macbecin) reversed v-Src transformed cells to normal phenotypes, and Bcr-abl was subsequently suggested to be the molecular target for the treatment of chronic myelogenous leukemia through a study using herbimycin A for its selective antioncogenic activity. In 1994, these ansamycins were found to bind to Hsp90 and to cause the degradation of client proteins including Src kinases; further efforts to develop anticancer drugs were made using geldanamycin analogs, and 17AAG was chosen as the best candidate for clinical trials. The number of novel natural products isolated from microbial origins is continuing to increase and is doubling every 10 years. Thus, scree ning of bioactive substances from natural origins, using assays including defined targets, and developing leads toward drugs via optimized derivatization is a conventional but still promising strategy for drug discovery and development.

Keywords: Hsp90, ansamycins, geldanamycin, 17AAG, myelogenous

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Article Details

VOLUME: 3
ISSUE: 5
Year: 2003
Page: [325 - 330]
Pages: 6
DOI: 10.2174/1568009033481796
Price: $58