Abstract
Hsp90 allows cancer cells to tolerate the many components of dysregulated pathways in a transformationspecific manner by interacting with several client substrates, such as kinases, hormone receptors and transcription factors that are directly involved in driving multistep malignancy, and also with mutated oncogenic proteins required for the transformed phenotype. This distinctive broad involvement in maintaining the transformed phenotype has suggested Hsp90 as an important target in cancer therapy. Discovery of pharmacological agents that selectively inhibit its function have aided in probing the biological functions of Hsp90 at the molecular level and in validating it as a novel target for anticancer drug action. Two natural product derivatives, 17-allylamino-17-desmethoxy-geldanamycin (17AAG) and 17- dimethylaminoethylamino-17-desmethoxy-geldanamycin (17DMAG) have further entered clinical trials, proving that Hsp90 may be modulated pharmacologically without causing target related toxicities in humans. In spite of their usefulness as proof-of-principle compounds, the clinical use of these two agents has been encumbered with some limitations due to their structural characteristics and also to less than optimal pharmacological profiles. Thus, the identification of Hsp90 inhibitors with improved structural characteristics and better pharmacological profiles is a major focus of interest in the field. One such emerging class is the purine-scaffold series. This review intends to inform the reader on efforts ranging from the discovery to their clinical translation.
Keywords: N-terminal ATPase pocket, Hsp90 inhibitors, purine-scaffold, 8-sulfanylpurines, tumor growth
Current Topics in Medicinal Chemistry
Title: Discovery and Development of Purine-Scaffold Hsp90 Inhibitors
Volume: 6 Issue: 11
Author(s): Gabriela Chiosis
Affiliation:
Keywords: N-terminal ATPase pocket, Hsp90 inhibitors, purine-scaffold, 8-sulfanylpurines, tumor growth
Abstract: Hsp90 allows cancer cells to tolerate the many components of dysregulated pathways in a transformationspecific manner by interacting with several client substrates, such as kinases, hormone receptors and transcription factors that are directly involved in driving multistep malignancy, and also with mutated oncogenic proteins required for the transformed phenotype. This distinctive broad involvement in maintaining the transformed phenotype has suggested Hsp90 as an important target in cancer therapy. Discovery of pharmacological agents that selectively inhibit its function have aided in probing the biological functions of Hsp90 at the molecular level and in validating it as a novel target for anticancer drug action. Two natural product derivatives, 17-allylamino-17-desmethoxy-geldanamycin (17AAG) and 17- dimethylaminoethylamino-17-desmethoxy-geldanamycin (17DMAG) have further entered clinical trials, proving that Hsp90 may be modulated pharmacologically without causing target related toxicities in humans. In spite of their usefulness as proof-of-principle compounds, the clinical use of these two agents has been encumbered with some limitations due to their structural characteristics and also to less than optimal pharmacological profiles. Thus, the identification of Hsp90 inhibitors with improved structural characteristics and better pharmacological profiles is a major focus of interest in the field. One such emerging class is the purine-scaffold series. This review intends to inform the reader on efforts ranging from the discovery to their clinical translation.
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Cite this article as:
Chiosis Gabriela, Discovery and Development of Purine-Scaffold Hsp90 Inhibitors, Current Topics in Medicinal Chemistry 2006; 6 (11) . https://dx.doi.org/10.2174/156802606777812013
DOI https://dx.doi.org/10.2174/156802606777812013 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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