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
Current Cancer Drug Targets
Title: Natural Product Origins of Hsp90 Inhibitors
Volume: 3 Issue: 5
Author(s): Yoshimasa Uehara
Affiliation:
Keywords: Hsp90, ansamycins, geldanamycin, 17AAG, myelogenous
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.
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Cite this article as:
Uehara Yoshimasa, Natural Product Origins of Hsp90 Inhibitors, Current Cancer Drug Targets 2003; 3 (5) . https://dx.doi.org/10.2174/1568009033481796
DOI https://dx.doi.org/10.2174/1568009033481796 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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