Article

4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer.

Vernalis Ltd., Granta Park, Great Abington, Cambridge CB21 6GB, U.K. p.brough@ vernalis.com
Journal of Medicinal Chemistry (impact factor: 5.25). 02/2008; 51(2):196-218. DOI:10.1021/jm701018h pp.196-218
Source: PubMed

ABSTRACT Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure-activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity for Hsp90, as measured in a fluorescence polarization (FP) competitive binding assay, and are active in cancer cell lines where they inhibit proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Compound 40f (VER-52296/NVP-AUY922) is potent in the Hsp90 FP binding assay (IC50 = 21 nM) and inhibits proliferation of various human cancer cell lines in vitro, with GI50 averaging 9 nM. Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by approximately 50%.

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Keywords

40f inhibits tumor growth
 
cancer cell lines
 
characteristic profile
 
Compound 40f
 
exhibit
 
FP
 
Hsp90 FP binding assay
 
Hsp90 molecular chaperone
 
human colon cancer xenograft model
 
Inhibitors
 
oncogenic proteins
 
potent small-molecule inhibitors
 
potential chemotherapeutic agents
 
various human cancer cell lines