In silico transcriptome screens identify epidermal growth factor receptor inhibitors as therapeutics for noise-induced hearing loss.

Noise-induced hearing loss (NIHL) is a common sensorineural hearing impairment that lacks U.S. Food and Drug Administration-approved drugs. To fill the gap in effective screening models, we used an in silico transcriptome-based drug screening approach, identifying 22 biological pathways and 64 potential small molecule treatments for NIHL. Two of these, afatinib and zorifertinib [epidermal growth factor receptor (EGFR) inhibitors], showed efficacy in zebrafish and mouse models. Further tests with EGFR knockout mice and EGF-morpholino zebrafish confirmed their protective role against NIHL. Molecular studies in mice highlighted EGFR's crucial involvement in NIHL and the protective effect of zorifertinib. When given orally, zorifertinib was found in the perilymph with favorable pharmacokinetics. In addition, zorifertinib combined with AZD5438 (a cyclin-dependent kinase 2 inhibitor) synergistically prevented NIHL in zebrafish. Our results underscore the potential for in silico transcriptome-based drug screening in diseases lacking efficient models and suggest EGFR inhibitors as potential treatments for NIHL, meriting clinical trials.

In Silico Transcriptome-based Screens Identify Epidermal Growth Factor Receptor Inhibitors as Therapeutics for Noise-induced Hearing Loss.

Noise-Induced Hearing Loss (NIHL) represents a widespread disease for which no therapeutics have been approved by the Food and Drug Administration (FDA). 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. Highlights: In silico transcriptome-based drug screens identify pathways and drugs against NIHL.EGFR signaling is activated by noise but reduced by zorifertinib in mouse cochleae.Afatinib, zorifertinib and EGFR knockout protect against NIHL in mice and zebrafish.Orally delivered zorifertinib has inner ear PK and synergizes with a CDK2 inhibitor.