: Hsp90 is a molecular chaperone responsible for folding nascent polypeptides into their biologically active, three-dimensional conformations. Disruption of the Hsp90 protein folding process results in the simultaneous inhibition of multiple enzymes that are essential for malignant cell growth. In fact, proteins represented in all six hallmarks of cancer are dependent on Hsp90 for conformational activation, and several of these Hsp90 client proteins are individually sought after cancer chemotherapeutic targets. Consequently, Hsp90 inhibition offers a promising new target for the development of anticancer chemotherapeutic agents because multiple signaling pathways can be simultaneously inhibited by disruption of the Hsp90 protein folding machinery. This application aims to develop new high-throughput assays for the identification of new lead compounds that inhibit Hsp90. A cell lysate assay will be developed to screen for inhibitors that prevent the renaturation of a well-studied Hsp90 client protein that has excellent bio-luminescence properties. It is proposed that molecules capable of inhibiting this renaturation process will be subsequently analyzed for their method of Hsp90 inhibition by two independent assays aimed at identifying both N- and C-terminal ATP binding site inhibitors. Alternatively, each of these assays should be independently capable of identifying new inhibitors of Hsp90 in a complimentary manner. At the completion of this project, we expect to provide three independent assays for high-throughput detection and evaluation of inhibitors that disrupt the Hsp90 protein folding process. The therapeutic potential of these compounds could be immense, as subsequent modification of these lead compounds should lead to the development of novel high-affinity Hsp90 antagonists for the treatment of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA114393-02
Application #
7032283
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Song, Min-Kyung H
Project Start
2005-03-16
Project End
2008-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
2
Fiscal Year
2006
Total Cost
$214,047
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
Ghosh, Suman; Shinogle, Heather E; Garg, Gaurav et al. (2015) Hsp90 C-terminal inhibitors exhibit antimigratory activity by disrupting the Hsp90?/Aha1 complex in PC3-MM2 cells. ACS Chem Biol 10:577-90
Zhao, Jinbo; Zhao, Huiping; Hall, Jessica A et al. (2014) Triazole Containing Novobiocin and Biphenyl Amides as Hsp90 C-Terminal Inhibitors. Medchemcomm 5:1317-1323
Hastings, Jedidiah M; Hadden, M Kyle; Blagg, Brian S J (2008) Synthesis and evaluation of derrubone and select analogues. J Org Chem 73:369-73
Hadden, M Kyle; Blagg, Brian S J (2007) Cytotoxic small molecule dimers and their inhibitory activity against human breast cancer cells. Bioorg Med Chem Lett 17:5063-7
Hadden, M Kyle; Galam, Lakshmi; Gestwicki, Jason E et al. (2007) Derrubone, an inhibitor of the Hsp90 protein folding machinery. J Nat Prod 70:2014-8
Galam, Lakshmi; Hadden, M Kyle; Ma, Zeqiang et al. (2007) High-throughput assay for the identification of Hsp90 inhibitors based on Hsp90-dependent refolding of firefly luciferase. Bioorg Med Chem 15:1939-46
Avila, Christopher; Hadden, M Kyle; Ma, Zeqiang et al. (2006) High-throughput screening for Hsp90 ATPase inhibitors. Bioorg Med Chem Lett 16:3005-8
Hadden, M Kyle; Lubbers, Donna J; Blagg, Brian S J (2006) Geldanamycin, radicicol, and chimeric inhibitors of the Hsp90 N-terminal ATP binding site. Curr Top Med Chem 6:1173-82
Avila, Christopher; Kornilayev, Boris A; Blagg, Brian S J (2006) Development and optimization of a useful assay for determining Hsp90's inherent ATPase activity. Bioorg Med Chem 14:1134-42