Repurposing an FDA Approved Drug, B-Raf Inhibitor Dabrafenib, for Protection from Cisplatin- and Noise-Induced Hearing Loss

项目总结/摘要 噪音、衰老、抗生素和化疗导致的听力损失影响着7亿人 在世界范围内，还没有FDA批准的药物来预防它。这项建议是优化FDA批准的， 口服生物可利用的小分子B-Raf激酶抑制剂达拉非尼（TAFINLAR），用于预防或治疗顺铂- 和噪声性听力损失（分别为CIHL和NIHL）。充分利用 CIHL和NIHL中激活的分子途径，对4，385种生物活性物质进行无偏高通量筛选， 化合物（Teitz等人，2018）和187种高度特异性激酶抑制剂（未发表），可减少顺铂- 在内耳细胞系（HEI-OC 1）中诱导的细胞死亡显示达拉菲尼为最佳命中。Dabrafenib是一种有效的 用于治疗晚期黑色素瘤和非小细胞肺的B-Raf激酶的选择性小分子抑制剂 carcinoma.这种药物在体外可预防顺铂诱导的毛细胞死亡，IC50为30 nM，治疗指数为 > 2000，比其他四种基准耳保护剂（硫代硫酸钠、依布硒啉、D- 甲硫氨酸和地塞米松;初步数据和Teitz等人，JEM 2018）。三种额外的B-Raf抑制剂 两种MEK 1/2抑制剂（直接位于B-Raf激酶下游）也阻止了顺铂诱导的毛细胞凋亡。 耳蜗移植死亡。此外，口服达拉非尼在CIHL小鼠模型中提供了显著的保护作用。 和NIHL。向小鼠施用的达拉非尼的日剂量在批准用于慢性人类肿瘤的范围内。 治疗（6 - 12个月）。因此，我们假设达拉非尼可以迅速地用于口服给药 预防CIHL和NIHL。因为达拉非尼的临床前和临床毒性特征已经被 经FDA批准，拟议的工作重点是必要的非临床实验，以确定 达拉菲尼的疗效加快转化为临床使用，使CIHL和NIHL高风险患者受益。 测试不同的时间表，以防止CIHL和NIHL，如本提案所述，将允许识别 最重要的人体临床试验方案。这项研究还将揭示一种新的细胞途径和分子机制。 靶向B-Raf激酶用于耳保护。这些研究的完成将导致FDA的第一个- 用于预防和治疗听力损失的批准药物。

PROJECT SUMMARY/ABSTRACT Hearing loss caused by noise, aging, antibiotics and chemotherapy affects seven hundred million people worldwide, yet there are no FDA-approved drugs to prevent it. This proposal is to optimize an FDA-approved, orally bioavailable small molecule B-Raf kinase inhibitor, dabrafenib (TAFINLAR), to prevent or treat cisplatin- and noise-induced hearing loss (CIHL and NIHL, respectively). Taking advantage of the significant overlap in the molecular pathways activated in CIHL and NIHL, unbiased high-throughput screens of 4,385 bioactive compounds (Teitz et al., 2018) and 187 highly-specific kinase inhibitors (unpublished) that reduced cisplatin- induced cell-death in an inner ear cell line (HEI-OC1) revealed dabrafenib as the best hit. Dabrafenib is a potent selective small molecule inhibitor of B-Raf kinase for treating advanced melanoma and non-small cell lung carcinoma. This drug prevented cisplatin-induced hair cell death in vitro, with IC50 of 30 nM and therapeutic index >2000, and 70-3,280 times better than four other benchmark otoprotectants (sodium thiosulfate, ebselen, D- methionine and dexamethasone; preliminary data and Teitz et al., JEM 2018). Three additional B-Raf inhibitors and two MEK1/2 inhibitors (directly downstream from B-Raf kinase) also prevented cisplatin-induced hair cell death in cochlear explants. Furthermore, oral dabrafenib provided significant protection in mouse models of CIHL and NIHL. The daily dose of dabrafenib administered to mice was in the range approved for chronic human treatment (6-12 months). Therefore, we hypothesize that dabrafenib can be rapidly repurposed for oral delivery to humans to prevent CIHL and NIHL. Because preclinical and clinical toxicity profiles of dabrafenib are already approved by FDA, the proposed work focuses on the necessary nonclinical experiments for determining dabrafenib’s efficacy for expedited translation into clinical use to benefit patients at high risk of CIHL and NIHL. Testing the different schedules to prevent CIHL and NIHL as described in this proposal will allow to identify the most important regimens for human clinical trials. The study will also reveal a new cellular pathway and molecular target B-Raf kinase for otoprotection. The completion of the studies will lead to one of the first FDA- approved drugs repurposed for the prevention and treatment of hearing loss.