The 90 kDa heat shock proteins (Hsp90) are responsible for the maturation of approximately 200 client protein substrates, most of which are associated with signaling cascades that regulate cellular growth and proliferation. Therefore, Hsp90 inhibition provides a novel approach toward the treatment of cancer as numerous signaling cascades can be derailed through inhibition of the Hsp90-dependent protein folding process. There are four Hsp90 isoforms. However, the ability to selectively inhibit each of these has not been realized. Through collaborative studies, we propose to develop selective inhibitors of Hsp90 isoforms through rationally designed analogues that bind to the N-terminal ATP-binding site, that selectively disrupt Hsp90/co- chaperone interactions, and through modification of the natural product, geldanamycin. Such approaches are likely to afford compounds that exhibit greater selectivity, reduced toxicity, and identify isoform-dependent client protein substrates. Culmination of such data will provide a platform on which further isoform-selective inhibitors can be pursued for the development of new cancer chemotherapeutics.

Public Health Relevance

The development of cancer chemotherapeutics that exhibit minimal toxicity represents an emerging paradigm in medicinal chemistry/drug design. Utilizing the techniques described in this application, inhibitors of the Hsp90 protein folding process will be rationally developed with the aim of increasing selectivity and minimizing toxicity in the hopes that more efficacious compounds can be developed for the treatment of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA109265-08
Application #
8525090
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Misra, Raj N
Project Start
2004-07-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
8
Fiscal Year
2013
Total Cost
$220,737
Indirect Cost
$70,576
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Di, Xiao-Jing; Wang, Ya-Juan; Han, Dong-Yun et al. (2016) Grp94 Protein Delivers γ-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
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
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
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
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
Ghosh, Suman; Shinogle, Heather E; Garg, Gaurav et al. (2015) Hsp90 C-terminal inhibitors exhibit antimigratory activity by disrupting the Hsp90α/Aha1 complex in PC3-MM2 cells. ACS Chem Biol 10:577-90
Hall, Jessica A; Kusuma, Bhaskar Reddy; Brandt, Gary E L et al. (2014) Cruentaren A binds F1F0 ATP synthase to modulate the Hsp90 protein folding machinery. ACS Chem Biol 9:976-85
Muth, Aaron; Crowley, Vincent; Khandelwal, Anuj et al. (2014) Development of radamide analogs as Grp94 inhibitors. Bioorg Med Chem 22:4083-98

Showing the most recent 10 out of 34 publications