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Design, synthesis, and evaluation of small molecule Hsp90 probes

Design, synthesis, and evaluation of small molecule Hsp90 probes

Authors :
Hongliang Zong
James H. Ahn
Monica L. Guzman
Pallav D. Patel
Anna Rodina
Danuta Zatorska
Kamalika Moulick
Tony Taldone
Gabriela Chiosis
Source :
Bioorganicmedicinal chemistry. 19(8)
Publication Year :
2010

Abstract

A number of compounds from different chemical classes are known to bind competitively to the ATP-pocket of Hsp90 and inhibit its chaperone function. The natural product geldanamycin was the first reported inhibitor of Hsp90 and since then synthetic inhibitors from purine, isoxazole and indazol-4-one chemical classes have been discovered and are currently or soon to be in clinical trials for the treatment of cancer. In spite of a similar binding mode to Hsp90, distinct biological profiles were demonstrated amongst these molecules, both in vitro and in vivo. To better understand the molecular basis for these dissimilarities, we report here the synthesis of chemical tools for three Hsp90 inhibitor classes. These agents will be useful for probing tumor-by-tumor the Hsp90 complexes isolated by specific inhibitors. Such information will lead to better understanding of tumor specific molecular markers to aid in their clinical development. It will also help to elucidate the molecular basis for the biological differences observed among Hsp90 inhibitors.

Details

ISSN :
14643391
Volume :
19
Issue :
8
Database :
OpenAIRE
Journal :
Bioorganicmedicinal chemistry
Accession number :
edsair.doi.dedup.....91a26b820e44d276e66efb89a7206e9f