The 90 kDa heat shock proteins are proving to be extraordinary cancer chemotherapeutic targets as evidenced by the fact that more than 20 clinical trials are currently in progress. Unfortunately, all of these trials are based upon N-terminal inhibitors, primarily geldanamycin- derived, which exhibit serious formulation, scheduling and dosing difficulties as these compounds induce Hsp's at the same concentration they induce client protein degradation. Previous studies by Neckers and coworkers determined that Hsp90 contains a C-terminal ATP binding site that bound coumarin antibiotics competitively versus ATP. Like N-terminal inhibitors, inhibitors of the C-terminal binding domain also cause the degradation of Hsp90-dependent client proteins required for tumor cell growth and proliferation. A major drawback of the coumarin antibiotics is that they bind weakly to Hsp90 (IC50 approximately 700 micromolar);however, recent studies by our group have led to compounds >1000 fold more active than these natural products. Through extensive studies and elucidation of the C- terminal binding site, we have learned how to modulate Hsp90 in ways not previously realized. Thus, we have developed compounds that induce Hsp's at low concentrations that refold denatured proteins as a new method to treat various neurodegenerative diseases. In contrast, we have constructed molecules that inhibit Hsp90 without inducing Hsp's, and therefore provide a mechanism by which to bypass difficulties observed with N- terminal inhibitors in the clinic. In this application we propose to develop anticancer agents based on our recently elucidated C-terminal binding site in an effort to produce agents suitable for clinical evaluation. In addition, we plan to investigate the most active compounds in additional in vivo models of cancer

Public Health Relevance

Current Hsp90 inhibitors in clinical trials exhibit detrimental properties that are proving difficult to overcome. We have identified molecules that do not exhibit these deleterious properties and have proven to be exceptional in preliminary animal models of cancer. Therefore, the goal of this proposal is to attack multiple cancer-enabling enzymes by inhibiting Hsp90 at a new location and to produce new clinical candidates for the treatment of cancer

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA120458-08
Application #
8516875
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Misra, Raj N
Project Start
2006-05-19
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
8
Fiscal Year
2013
Total Cost
$323,039
Indirect Cost
$77,261
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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Mays, Jared R; Hill, Stephanie A; Moyers, Justin T et al. (2010) The synthesis and evaluation of flavone and isoflavone chimeras of novobiocin and derrubone. Bioorg Med Chem 18:249-66
Peterson, Laura B; Blagg, Brian S J (2010) Click chemistry to probe Hsp90: Synthesis and evaluation of a series of triazole-containing novobiocin analogues. Bioorg Med Chem Lett 20:3957-60
Donnelly, Alison C; Mays, Jared R; Burlison, Joseph A et al. (2008) The design, synthesis, and evaluation of coumarin ring derivatives of the novobiocin scaffold that exhibit antiproliferative activity. J Org Chem 73:8901-20

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