Discovery and development of purine-scaffold Hsp90 inhibitors Journal Article

Author: Chiosis, G.
Article Title: Discovery and development of purine-scaffold Hsp90 inhibitors
Abstract: Hsp90 allows cancer cells to tolerate the many components of dysregulated pathways in a transformation-specific 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. © 2006 Bentham Science Publishers Ltd.
Keywords: unclassified drug; oncoprotein; clinical trial; review; gastrointestinal hemorrhage; nonhuman; antineoplastic agents; drug targeting; antineoplastic agent; mutant protein; protein function; neoplasms; animals; liver toxicity; breast cancer; transcription factor; drug potency; drug structure; drug design; drug synthesis; structure activity relation; cancer therapy; biological activity; cell transformation; cancer cell; heat shock protein 90 inhibitor; heat shock protein 90; drug clearance; hsp90 heat-shock proteins; stomach cancer; models, molecular; purines; molecular structure; purine derivative; drug blood level; tumor growth; natural product; hormone receptor; ic 50; phosphotransferase; adenine; ansamycin derivative; hsp90 inhibitors; purine-scaffold; cnf 1010; 17 allylamino 17 demethoxygeldanamycin; 17 dimethylaminoethylamino 17 demethoxygeldanamycin; ipi 504; 8-sulfanylpurines; n-terminal atpase pocket; kos 953; neopentylamine; tert butylamine derivative; anisoles
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: 1183
End Page: 1191
Language: English
DOI: 10.2174/156802606777812013
PUBMED: 16842155
PROVIDER: scopus
Notes: --- - "Cited By (since 1996): 35" - "Export Date: 4 June 2012" - "CODEN: CTMCC" - "Source: Scopus"
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  1. Gabriela Chiosis
    216 Chiosis