No. 8

Title: Developing drugs against hearing loss

Speaker: Jian Zuo

Co-Founder / CEO, Ting Therapeutics

Host：Lin Mei

          Chinese Institutes for Medical Research, Beijing

Time：10:00-11:30 a.m., Oct. 10, 2023 (Tuesday)

Location: Room 1322, North Tower, Basic Research Building, Capital Medical University (首都医科大学基础科研楼北楼1322会议室)

Abstract：

Hearing Loss represents a widespread disease for which no effective therapeutics have been approved by the Food and Drug Administration (FDA). For cisplatin- and antibiotics-induced hearing loss, we screened existing small molecule libraries for protection against cisplatin induced cell loss by using multiple in vitro and in vivo zebrafish lateral line methods, many of the drug hits were further characterized in mouse models in vivo. For noise-induced hearing loss (NIHL), addressing the conspicuous void of efficacious in vitro or animal models for high throughput pharmacological screening, we utilized an in silico transcriptome-oriented drug screening strategy, unveiling 22 biological pathways and 64 promising small molecule candidates for NIHL protection. Afatinib and zorifertinib, both inhibitors of the Epidermal Growth Factor Receptor (EGFR), were validated for their protective efficacy against NIHL in experimental zebrafish and murine models. This protective effect was further confirmed with EGFR conditional knockout mice and EGF knockdown zebrafish, both demonstrating protection against NIHL. Molecular analysis using Western blot and kinome signaling arrays on adult mouse cochlear lysates unveiled the intricate involvement of several signaling pathways, with particular emphasis on EGFR and its downstream pathways being modulated by noise exposure and zorifertinib treatment. Administered orally, zorifertinib was successfully detected in the perilymph fluid of the inner ear in mice with favorable pharmacokinetic attributes. Zorifertinib, in conjunction with AZD5438 – a potent inhibitor of cyclin-dependent kinase 2 – produced synergistic protection against NIHL in the zebrafish model. Collectively, our findings underscore the potential application of in silico transcriptome-based drug screening for diseases bereft of efficient screening models and posit EGFR inhibitors as promising therapeutic agents warranting clinical exploration for combatting NIHL and other forms of hearing loss.

Representative publications:

1. CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss. Journal of Experimental Medicine, 2018; 215(4): 1187-1203.
2. BRAF Inhibition Protects Against Hearing Loss in Mice. Science Advances, 2020; 6: eabd0561.
3. Characterization of quinoxaline derivatives for protection against iatrogenic-induced hearing loss. JCI: Insight, 2021;6(5): e141561.
4. AZD5438-PROTAC: A Selective CDK2 Degrader that Protects Against Cisplatin- and Noise-Induced Hearing Loss. European Journal of Medicinal Chemistry, 2021; 226: 113849.
5. In Silico Transcriptome-based Screens Identify Epidermal Growth Factor Receptor 1 Inhibitors as Therapeutics for Noise-induced Hearing Loss. bioRxiv preprint doi:https://doi.org/10.1101/2023.06.07.544128