Discovery of in vivo small molecules for hearing protection against cisplatin and noise

项目概要： 到目前为止，美国食品和药物管理局（FDA）还没有批准用于预防 顺铂或噪声引起的听力损失。我们已经开发了一种无偏见的，表型药物筛选， 使用来自新生小鼠耳蜗的细胞系对顺铂耳毒性的保护。从库中 在4，359种独特的化合物中，包括844种FDA批准的药物，我们已经确定了一种最受欢迎的药物， 在耳蜗细胞系和耳蜗外植体培养中， 治疗指数（>200）和约150 nM的IC 50。我们已经证实，当局部注射到成年小鼠体内时， 通过鼓膜注射，这种顶击可以防止顺铂和噪音损伤。因此，我们有一个 经验证的top hit可防止顺铂和噪音引起的听力损失。在这里，我们建议优化 我们的最高打击，以产生一个铅化合物，通过改善当地的交付方法，并通过执行顺序 分析，包括药物化学、构效关系（SAR）、吸收、分布， 代谢、排泄、安全性/毒理学（ADMET）以及体内药代动力学（PK）和药效学 (PD)问题研究我们的顶级命中和它的类似物，在我们的流线型测定测试后，将作为候选 用于临床前和临床研究的化合物，当局部递送用于治疗 听力损失

PROJECT SUMMARY: 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.