Heat shock protein 90 (Hsp90) and Hsp70 are molecular chaperones that facilitate protein folding, maturation and clearance. It is well recognized that targeting Hsp90 and Hsp70 with small molecule drugs may improve proteostatic neurodegenerative diseases by enhancing the clearance of neurotoxic protein aggregates. However, we have identified that pharmacologically targeting molecular chaperones has therapeutic value in treating peripheral neuropathies whose etiology is independent of proteostasis. The traditional small molecule approach for targeting Hsp90 has relied on drugs that inhibit its N-terminal ATPase activity. Lamentably, the translational success of these drugs has been hindered by the complex chemical biology of targeting the Hsp90 N-terminal ATP binding site. In contrast, we have developed ?novologues? as small molecule inhibitors of the Hsp90 C-terminal domain that circumvent limitations that have confounded the clinical prospects of Hsp90 as a therapeutic target. Novologues are orally bioavailable and non-toxic molecules that promote a cytoprotective response that constitutes a paradigm shift for the treatment of diabetic peripheral neuropathy (DPN) and potentially, demyelinating neuropathies (DymN). Our published and unpublished data support that novologues improve physiologic measures of DPN and DymN in an Hsp70- dependent manner by improving mitochondrial bioenergetics in DPN and inhibiting the induction of c-jun, a negative regulator of myelination, that contributes to DymN. Thus, our central hypothesis is that modulating the activity of molecular chaperones with novologues will provide an innovative and novel approach for the treatment of both DPN and some forms of DymN. Our efforts over the four years of NIH funding have led to the licensing of our lead novologue, KU-596, to a pharmaceutical company and its advancement to Phase I studies for treating DPN. To build upon this success, we have identified attributes and detriments of KU- 596.
Specific Aim 1 focuses on the rationale design and development of ?noviomimetics? as a new class of molecules that will improve on the chemical biology of novologues by increasing potency, requiring fewer synthetic steps and exhibiting better metabolic stability.
Specific Aim 2 will use two cell-based screening assays to examine the ability to improve mitochondrial bioenergetics in diabetic sensory neurons or increase the degradation of the transcription factor, c-jun. Importantly, we provide evidence that these biochemical readouts are prognostic for in vivo efficacy to improve DPN and DymN, respectively. Compounds that advance through the cell-based assay will undergo ADME screening to aid selecting candidates for in vivo testing in a mouse model of DPN and two models that recapitulate a human demyelinating motor neuropathy. The outcome of this work will extend the success of our drug development program and identify noviomimetics as a new class of neuroprotective compounds for treating peripheral neuropathies.

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 and potentially, other demyelinating diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS075311-06
Application #
9604912
Study Section
Drug Discovery for the Nervous System Study Section (DDNS)
Program Officer
Nuckolls, Glen H
Project Start
2017-11-23
Project End
2021-06-30
Budget Start
2017-11-23
Budget End
2018-06-30
Support Year
6
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Notre Dame
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
824910376
City
Notre Dame
State
IN
Country
United States
Zip Code
46556
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
Forsberg, Leah K; Anyika, Mercy; You, Zhenyuan et al. (2018) Development of noviomimetics that modulate molecular chaperones and manifest neuroprotective effects. Eur J Med Chem 143:1428-1435
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
Sofis, Michael J; Jarmolowicz, David P; Kaplan, Sam V et al. (2017) KU32 prevents 5-fluorouracil induced cognitive impairment. Behav Brain Res 329:186-190
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
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
Emery, S M; Dobrowsky, R T (2016) Promoting Neuronal Tolerance of Diabetic Stress: Modulating Molecular Chaperones. Int Rev Neurobiol 127:181-210

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