To date, there are no drugs approved by the US Food and Drug Administration (FDA) for protection against cisplatin- or noise-induced hearing loss. We have developed an unbiased, phenotypic drug screen for protection against cisplatin ototoxicity, using a cell line derived from neonatal mouse cochleae. From a library of 4,359 unique compounds, including 844 FDA-approved drugs, we have identified a top hit that exerts strong protection against cisplatin ototoxicity in the cochlear cell line and cochlear explant culture, with an excellent therapeutic index (>200) and an IC50 of ~150 nM. We have confirmed that when locally delivered to adult mice via injection through the eardrum, this top hit protects against cisplatin and noise injury. Therefore, we have a validated top hit that protects against cisplatin- and noise-induced hearing loss. Here we propose to optimize our top hit to generate a lead compound by improving local delivery methods and by performing sequential analyses, including medicinal chemistry, structure-activity relationship (SAR), absorption, distribution, metabolism, excretion, safety/toxicology (ADMET), and in vivo pharmacokinetics (PK) and pharmacodynamics (PD) studies. Our top hit and its analogs, after testing in our streamlined assays, will serve as candidate compounds for preclinical and clinical studies of their safety and efficacy when locally delivered for treatment of hearing loss.

Public Health Relevance

More than 360 million people worldwide suffer from hearing loss induced by chemotherapy, antibiotics, or noise; however, there are no FDA-approved drugs to protect against this prevalent and costly disability. We have identified a top compound that provides protection against cisplatin- and noise-induced hearing loss in vivo when delivered locally into the mouse middle ear. Our proposed studies will structurally optimize the top compound and develop analogs that show the best in vivo properties, for subsequent preclinical and clinical assessment of locally delivered therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
7R01DC015444-03
Application #
9672287
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Freeman, Nancy
Project Start
2016-09-01
Project End
2019-08-31
Budget Start
2018-04-01
Budget End
2018-08-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Creighton University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
053309332
City
Omaha
State
NE
Country
United States
Zip Code
68178
Steyger, Peter S; Cunningham, Lisa L; Esquivel, Carlos R et al. (2018) Editorial: Cellular Mechanisms of Ototoxicity. Front Cell Neurosci 12:75
Teitz, Tal; Fang, Jie; Goktug, Asli N et al. (2018) CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss. J Exp Med 215:1187-1203
Hazlitt, Robert A; Min, Jaeki; Zuo, Jian (2018) Progress in the Development of Preventative Drugs for Cisplatin-Induced Hearing Loss. J Med Chem 61:5512-5524
Walters, Bradley J; Coak, Emily; Dearman, Jennifer et al. (2017) In Vivo Interplay between p27Kip1, GATA3, ATOH1, and POU4F3 Converts Non-sensory Cells to Hair Cells in Adult Mice. Cell Rep 19:307-320
Ban, David; Iconaru, Luigi I; Ramanathan, Arvind et al. (2017) A Small Molecule Causes a Population Shift in the Conformational Landscape of an Intrinsically Disordered Protein. J Am Chem Soc 139:13692-13700
Zheng, Fei; Zuo, Jian (2017) Cochlear hair cell regeneration after noise-induced hearing loss: Does regeneration follow development? Hear Res 349:182-196
Wood, Megan B; Zuo, Jian (2017) The Contribution of Immune Infiltrates to Ototoxicity and Cochlear Hair Cell Loss. Front Cell Neurosci 11:106
Lukashkina, Victoria A; Yamashita, Tetsuji; Zuo, Jian et al. (2017) Amplification mode differs along the length of the mouse cochlea as revealed by connexin 26 deletion from specific gap junctions. Sci Rep 7:5185
Teitz, Tal; Goktug, Asli N; Chen, Taosheng et al. (2016) Development of Cell-Based High-Throughput Chemical Screens for Protection Against Cisplatin-Induced Ototoxicity. Methods Mol Biol 1427:419-30