The etiology of diabetic peripheral neuropathy (DPN) initiates from an inter-related series of metabolic and vascular insults that ultimately contribute to sensory neuron degeneration. In the quest to pharmacologically manage DPN, small molecule inhibitors have been developed to target proteins regarded as """"""""diabetes specific"""""""" as well as those that increase in multiple disease states. Such efforts have not proven successful, suggesting the identification of novel targets that play a fundamental role in regulating protein integrity and preserving nerve function in the diabetic state may represent a new paradigm. Heat shock protein 90 (Hsp90) is a molecular chaperone that binds """"""""client proteins"""""""" and promotes their folding into biologically active structures. It is also the master regulator of a cytoprotective """"""""heat shock response"""""""", which aids the refolding of aggregated and damaged proteins that occur upon cell stress. Both the N- and C-terminal ATP binding domains of Hsp90 regulate its interaction with proteins. N-terminal inhibitors of Hsp90 exhibit potent cytotoxicity against tumor cells and are in clinical trials, but these compounds also induce a cytoprotective """"""""heat shock response"""""""" at concentrations necessary for cytotoxicity. In contrast, we have developed potent small molecule inhibitors of the Hsp90 C-terminal domain whose neuroprotective efficacy is manifested at concentrations far below those necessary to induce neuro-toxicity. The lead compound for these inhibitors, KU- 32, is based upon novobiocin. KU-32 protects against hyperglycemia-induced death of sensory neurons and can attenuate several physiologic indices of DPN in mice through induction of the heat shock response. Unfortunately, this molecule requires significant synthetic preparation, thus preventing full elucidation of structure-activity relationships and limiting its use in animals/humans. Thus, the goal of this proposal is to provide new compounds derived from KU-32 that exhibit better neuroprotective activity and can be prepared in a minimal number of synthetic procedures. An initial screen will identify compounds with increased efficacy relative to KU-32 and lead candidates will be tested for protection against glycemic stress of sensory neurons, followed by animal studies of DPN in both wild-type and Hsp70 knockout mice. The outcome of this work will further develop and identify small molecule C-terminal Hsp90 inhibitors that decrease neurodegeneration in the absence of significant neurotoxicity.

Public Health Relevance

Diabetic neuropathy is a common complication of diabetes that develops in about 60% of the approximately 24 million Americans afflicted with diabetes. Despite the impact of diabetic neuropathy on decreasing the quality of life, the existing FDA approved treatments are limited to drugs originally targeted to treat depression (Cymbalta) and convulsions (Lyrica). This project focuses on optimizing the effectiveness of a new class of therapeutics for the direct treatment of diabetic neuropathy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS075311-02
Application #
8413041
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (56))
Program Officer
Gwinn, Katrina
Project Start
2012-04-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$306,763
Indirect Cost
$95,669
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; 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
Emery, S M; Dobrowsky, R T (2016) Promoting Neuronal Tolerance of Diabetic Stress: Modulating Molecular Chaperones. Int Rev Neurobiol 127:181-210
Qian, Pengxu; He, Xi C; Paulson, Ariel et al. (2016) The Dlk1-Gtl2 Locus Preserves LT-HSC Function by Inhibiting the PI3K-mTOR Pathway to Restrict Mitochondrial Metabolism. Cell Stem Cell 18:214-28
Dobrowsky, Rick T (2016) Targeting the Diabetic Chaperome to Improve Peripheral Neuropathy. Curr Diab Rep 16:71
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
Ma, Jiacheng; Farmer, Kevin L; Pan, Pan et al. (2014) Heat shock protein 70 is necessary to improve mitochondrial bioenergetics and reverse diabetic sensory neuropathy following KU-32 therapy. J Pharmacol Exp Ther 348:281-92
Zhao, Huiping; Anyika, Mercy; Girgis, Antwan et al. (2014) Novologues containing a benzamide side chain manifest anti-proliferative activity against two breast cancer cell lines. Bioorg Med Chem Lett 24:3633-7

Showing the most recent 10 out of 15 publications