Hsp90 is a molecular chaperone responsible for folding nascent polypeptides into biologically active native structures. Many of the proteins dependent upon HspQO 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 HspQO 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 HspQO by a coupled assay (N-terminal ATP binding site), a cellular HspQO 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 #
5U01CA109265-05
Application #
7776956
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
2010-03-01
Budget End
2011-02-28
Support Year
5
Fiscal Year
2010
Total Cost
$246,281
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
Mishra, Sanket J; Ghosh, Suman; Stothert, Andrew R et al. (2017) Transformation of the Non-Selective Aminocyclohexanol-Based Hsp90 Inhibitor into a Grp94-Seletive Scaffold. ACS Chem Biol 12:244-253
Ghosh, Suman; Liu, Yang; Garg, Gaurav et al. (2016) Diverging Novobiocin Anti-Cancer Activity from Neuroprotective Activity through Modification of the Amide Tail. ACS Med Chem Lett 7:813-8
Anyika, Mercy; McMullen, Mason; Forsberg, Leah K et al. (2016) Development of Noviomimetics as C-Terminal Hsp90 Inhibitors. ACS Med Chem Lett 7:67-71
Ghosh, Suman; Shinogle, Heather E; Galeva, Nadezhda A et al. (2016) Endoplasmic Reticulum-resident Heat Shock Protein 90 (HSP90) Isoform Glucose-regulated Protein 94 (GRP94) Regulates Cell Polarity and Cancer Cell Migration by Affecting Intracellular Transport. J Biol Chem 291:8309-23
Di, Xiao-Jing; Wang, Ya-Juan; Han, Dong-Yun et al. (2016) Grp94 Protein Delivers ?-Aminobutyric Acid Type A (GABAA) Receptors to Hrd1 Protein-mediated Endoplasmic Reticulum-associated Degradation. J Biol Chem 291:9526-39
Khandelwal, Anuj; Crowley, Vincent M; Blagg, Brian S J (2016) Natural Product Inspired N-Terminal Hsp90 Inhibitors: From Bench to Bedside? Med Res Rev 36:92-118
Crowley, Vincent M; Khandelwal, Anuj; Mishra, Sanket et al. (2016) Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold. J Med Chem 59:3471-88
Ma, Jiacheng; Pan, Pan; Anyika, Mercy et al. (2015) Modulating Molecular Chaperones Improves Mitochondrial Bioenergetics and Decreases the Inflammatory Transcriptome in Diabetic Sensory Neurons. ACS Chem Neurosci 6:1637-48
Hall, Jessica A; Seedarala, Sahithi; Rice, Nichole et al. (2015) Cucurbitacin D Is a Disruptor of the HSP90 Chaperone Machinery. J Nat Prod 78:873-9
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

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