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 #
2U01CA120458-06
Application #
8184035
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Lees, Robert G
Project Start
2006-05-19
Project End
2015-06-30
Budget Start
2011-09-01
Budget End
2012-06-30
Support Year
6
Fiscal Year
2011
Total Cost
$369,318
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
Kumar Mv, Vasantha; Ebna Noor, Radwan; Davis, Rachel E et al. (2018) Molecular insights into the interaction of Hsp90 with allosteric inhibitors targeting the C-terminal domain. Medchemcomm 9:1323-1331
Zhang, Xinyue; Li, Chengyuan; Fowler, Stephen C et al. (2018) Targeting Heat Shock Protein 70 to Ameliorate c-Jun Expression and Improve Demyelinating Neuropathy. ACS Chem Neurosci 9:381-390
Zhang, Zheng; You, Zhenyuan; Dobrowsky, Rick T et al. (2018) Synthesis and evaluation of a ring-constrained Hsp90 C-terminal inhibitor that exhibits neuroprotective activity. Bioorg Med Chem Lett 28:2701-2704
Khandelwal, Anuj; Kent, Caitlin N; Balch, Maurie et al. (2018) Structure-guided design of an Hsp90? N-terminal isoform-selective inhibitor. Nat Commun 9:425
Garg, Gaurav; Zhao, Huiping; Blagg, Brian S J (2017) Design, synthesis and biological evaluation of alkylamino biphenylamides as Hsp90 C-terminal inhibitors. Bioorg Med Chem 25:451-457
Byrd, Katherine M; Kent, Caitlin N; Blagg, Brian S J (2017) Synthesis and Biological Evaluation of Stilbene Analogues as Hsp90 C-Terminal Inhibitors. ChemMedChem 12:2022-2029
Davis, Rachel E; Zhang, Zheng; Blagg, Brian S J (2017) A Scaffold Merging Approach to Hsp90 C-terminal Inhibition: Synthesis and Evaluation of a Chimeric Library. Medchemcomm 8:593-598
Forsberg, Leah K; Liu, Weiya; Holzbeierlein, Jeffrey et al. (2017) Modified biphenyl Hsp90 C-terminal inhibitors for the treatment of cancer. Bioorg Med Chem Lett 27:4514-4519
Garg, Gaurav; Forsberg, Leah K; Zhao, Huiping et al. (2017) Development of Phenyl Cyclohexylcarboxamides as a Novel Class of Hsp90 C-terminal Inhibitors. Chemistry 23:16574-16585
White, Peter T; Subramanian, Chitra; Zhu, Qing et al. (2016) Novel HSP90 inhibitors effectively target functions of thyroid cancer stem cell preventing migration and invasion. Surgery 159:142-51

Showing the most recent 10 out of 46 publications