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Using\n                  <jats:italic>in vivo<\/jats:italic>\n                  zebrafish lateral line screening combined with computational scaffold-hopping, we identified a novel class of otoprotective compounds. Starting from the ion channel modulator MR16728, we discovered compound 28510 as a potent lead compound. Compound 28510 provided robust, dose-dependent protection against AG-induced hair cell damage, restoring neuromast hair cell integrity to near-control levels in acute assays and demonstrating broad efficacy across clinically relevant AGs (gentamicin, tobramycin, amikacin, streptomycin) in chronic exposures. Importantly, 28510 exhibited a favorable therapeutic window, with low micromolar 50% hair cell protection concentration (HC\n                  <jats:sub>50<\/jats:sub>\n                  ) values consistently below toxicity thresholds. Mechanistically, FM1-43 and Texas Red-conjugated gentamicin uptake assays revealed that 28510 does not inhibit mechanotransduction (MET) channel-mediated AG entry, distinguishing it from current clinical candidates and pointing to a novel intracellular protective mechanism. 28510 preserved AG antibacterial activity in\n                  <jats:italic>E. coli<\/jats:italic>\n                  assays, supporting its translational compatibility as a co-therapeutic agent. Combinations of 28510 with related analogs did not yield synergistic protection; 28510 alone remained the most effective compound.\n                  <jats:italic>In silico<\/jats:italic>\n                  absorption, distribution, metabolism, and excretion (ADME) predictions further confirmed its highly favorable drug-like properties, including excellent intestinal and oral absorption. Together, these findings establish 28510 as a first-in-class, non-MET-mediated otoprotective lead with broad efficacy and a favorable therapeutic profile, highlighting a new strategy for preventing AG-induced hearing loss.\n                <\/jats:p>","DOI":"10.64898\/2026.05.14.725303","type":"posted-content","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:40:34Z","timestamp":1779151234000},"source":"Crossref","is-referenced-by-count":0,"title":["Discovery of a Novel Non-MET-Mediated Otoprotective Compound Against Aminoglycoside-Induced Ototoxicity"],"prefix":"10.64898","author":[{"given":"Elizabeth","family":"Kara","sequence":"first","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, Idaho State University, Meridian, ID 83642, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Nicolet","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, Idaho State University, Meridian, ID 83642, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaikh Emdadur","family":"Rahman","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, Idaho State University, Meridian, ID 83642, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Travis","family":"Hudok","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, Boise State University, Boise, ID 83725, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caleb","family":"Leach","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, Boise State University, Boise, ID 83725, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaden","family":"Falkner","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, Boise State 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