Hsp90 is a molecular chaperone responsible for folding nascent polypeptides into biologically active native structures. Many of the proteins dependent upon Hsp90 for conformational maturation are directly associated with malignant growth and proliferation. Inhibition of Hsp90 results in the destabilization of Hsp90-client protein complexes, resulting in ubiquitination and proteasomal degradation of the protein substrate. Consequently, inhibitors of Hsp90 represent a promising new approach toward the treatment of cancer because multiple chemotherapeutic targets can be simultaneously targeted. Two natural products with potent activity against Hsp90 have been co-crystallized with Hsp90 and the structures solved. Based on these co-crystal structures, new inhibitors of Hsp90 have been designed, docked to the N-terminal ATP binding site, and initial compounds synthesized. Preliminary testing of these compounds has resulted in the identification of several molecules with exceptional activity. In addition, new inhibitors of the C-terminal nucleotide binding site have been prepared and evaluated. One C-terminal inhibitor was shown to be >700 x more active than novobiocin. The objectives of this proposal are to prepare new Hsp90 inhibitors with increased affinity and solubility, as compared to the known natural product inhibitors. These molecules will be evaluated for their biological activity against Hsp90 by a coupled assay (N-terminal ATP binding site), a cellular Hsp90 client protein degradation assay, and by cytotoxicity studies. In collaboration with other researchers, the co-crystal structure of these molecules bound to Hsp90 will be solved and in vivo studies of these molecules will be performed in murine xenograft models of prostate and breast cancer. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01CA109265-01A2
Application #
7038182
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2006-03-15
Project End
2011-02-28
Budget Start
2006-03-15
Budget End
2007-02-28
Support Year
1
Fiscal Year
2006
Total Cost
$253,242
Indirect Cost
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
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