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

项目总结： 到目前为止，还没有得到美国食品和药物管理局(FDA)批准的药物用于预防 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查 使用来自新生小鼠耳蜗的细胞系保护顺铂耳毒性。从图书馆 在4359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化合物 在耳蜗细胞系和耳蜗外植体培养中对顺铂耳毒性的保护作用，具有良好的 治疗指数(&gt；200)和IC50为~150 NM。我们已经证实，当局部注射给成年小鼠时 通过鼓膜注射，这种最热门的药物可以防止顺铂和噪音伤害。因此，我们有一个 经过验证的TOP HIT可防止顺铂和噪声导致的听力损失。在这里，我们建议优化 我们的重头戏是通过改进当地的递送方法和进行连续的 分析，包括药物化学，构效关系，吸收，分布， 代谢、排泄、安全性/毒理学(ADMET)、体内药代动力学(PK)和药效学 (PD)研究。我们最热门的产品及其类似物，在我们简化的化验中进行测试后，将作为候选 用于临床前和临床研究的化合物，用于局部给药治疗癌症的安全性和有效性 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.