CDK2 inhibitors for protecting hearing loss

CDK2 抑制剂可保护听力损失

基本信息

批准号：
9907921
负责人：
Marisa L. Zallocchi
金额：
$ 22.07万
依托单位：
TING THERAPEUTICS LLC
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-09 至 2021-06-08
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9907921
关键词：
Adult Affect Animals Antioxidants Auditory Brainstem Responses Benchmarking Bioavailable Biological Assay CDK2 gene Cancer Patient Cell Death Cell Line Cell Survival China Cisplatin Cochlea Development Dexamethasone Dose Drug Delivery Systems Ear Europe Exhibits FVB Mouse Formulation Future Glutathione Metabolism Pathway Hair Cells Health Hearing Hearing Tests Histology Hong Kong Industry Injury Japan Labyrinth Legal patent Libraries Licensing Light Measures Mediation Medical Methionine Mitochondria Mus Noise Noise-Induced Hearing Loss Oral Patients Pharmaceutical Preparations Pharmacologic Substance Phase I Clinical Trials Phase II Clinical Trials Presbycusis Production Property Rattus Reactive Oxygen Species Resistance Rights Schedule Small Business Innovation Research Grant Societies Solid Neoplasm Testing Therapeutic Time Toxic effect United States Food and Drug Administration Work World Health Organization Zebrafish anti-cancer cancer clinical trial cancer therapy chemotherapy cisplatin induced hearing loss combat ebselen efficacy testing follow-up hearing impairment high throughput screening in vivo inhibitor/antagonist inner ear diseases kinase inhibitor lateral line local drug delivery male mouse model neoplastic cell neuromast olomoucine otoprotectant ototoxicity permanent hearing loss phase 2 study preclinical trial protective effect small molecule small molecule therapeutics sodium thiosulfate systemic toxicity therapeutic target vitamin metabolism volunteer

项目摘要

Title: CDK2 inhibitors for protecting hearing loss PROJECT SUMMARY Hearing loss is a major health concern in our society, affecting over 360 million people worldwide (World Health Organization, 2017). Cisplatin chemotherapy causes permanent hearing loss in 40-60% of treated cancer patients. To date, no drugs have been approved by the Food and Drug Administration (FDA) for protection from cisplatin-, noise-, or age-related hearing loss. Most candidate compounds currently in pre-clinical trials are related to antioxidants, vitamins, and glutathione metabolism, and thus many of these compounds, such as sodium thiosulfate, can interfere with cisplatin’s ability to kill the tumor cells. We recently conducted unbiased high-throughput screens of bioactive compounds (total of 4,385 unique compounds) in a cochlear ear cell line and identified cyclin dependent kinase-2 (CDK2) as an important therapeutic target for cisplatin-induced cell death and hearing loss. In the following focused screen of an additional 187 CDK2 inhibitors that have desirable drug-like properties, we identified AZD5438 as the top hit, exhibiting an IC50 of 540 nM in the cochlear cell line and an excellent IC50 of 5 nM ex vivo in mouse P3 cochlear explants treated with cisplatin. AZD5438 was the most potent CDK2 inhibitor tested in our cochlear explant studies. Furthermore, by local delivery of AZD5438 to adult FVB mice, the compound showed full protection against cisplatin-induced ototoxicity as measured by Auditory Brainstem Response (ABR) thresholds and cochlear histology. AZD5438 also protected against cisplatin induced hair cell loss in vivo in zebrafish lateral line neuromasts at 100 nM. Here we will evaluate the potential to repurpose the anti-cancer small molecule AZD5438, an orally bioavailable CDK2 inhibitor that has already been found to be tolerated in healthy male volunteers and solid-tumor patients in phase I and phase II clinical trials, for protection against cisplatin-induced hearing loss. Our Specific Aim is to test whether AZD5438 protects from cisplatin-induced hearing loss by systemic delivery in a mouse model. Our approach is to administer AZD5438 by oral gavage to adult FVB mice treated with cisplatin, measure their ABR thresholds and analyze their cochlear histology. The maximum non-toxic dose of oral AZD5438 will be experimentally determined and tested for hearing-protective effects. This work will shed light on the possibility of using AZD5438 in an oral formulation to combat cisplatin-induced hearing loss. In comparison to local delivery, oral delivery of an effective pharmaceutical product has the advantage of patient convenience. In the future, we will also test the efficacy of oral AZD5438 to protect from noise- and age- related hearing loss. If oral delivery of AZD5438 proves protective in this study, we will apply for IND-enabling SBIR phase II studies for cisplatin- induced hearing loss in cancer patients. As the main inventors for CDK2 inhibitors for hearing loss, both founders of Ting Therapeutics LLC have already obtained the exclusive patent rights for AZD5438 and filed patent applications in Europe, China, Japan and Hong Kong, and are negotiating for licensing the US patent rights. Oral delivery of AZD5438, if successful, has the potential to be a significant step forward in treating cancer patients against cisplatin-induced hearing loss.

标题：保护听力损失的CDK2抑制剂项目摘要听力损失是我们社会的主要健康问题，影响超过3.6亿人全球（世界卫生组织，2017年）。顺铂化疗导致永久性 40-60％的癌症患者的听力损失。迄今为止，尚未获得任何药物食品药品监督管理局（FDA），用于防止顺铂，噪声或与年龄有关的听力损失。临床前试验中目前的大多数候选化合物与抗氧化剂有关，维生素和谷胱甘肽代谢，因此许多这些化合物，例如钠硫代硫酸盐可以干扰顺铂杀死肿瘤细胞的能力。我们最近进行了生物活性化合物的无偏高通量屏幕（总计 4,385个独特的化合物）在耳蜗耳细胞系中，并鉴定出依赖细胞周期蛋白的激酶-2 （CDK2）是顺铂诱导的细胞死亡和听力丧失的重要治疗靶标。以下集合的屏幕，对具有理想药物样的额外的187个CDK2抑制剂属性，我们将AZD5438识别为最受欢迎的命中，在耳蜗细胞中表现出540 nm的IC50 用顺铂治疗的小鼠P3耳蜗外植体中的5 nm外体的线和出色的IC50。 AZD5438是我们人工耳蜗研究中测试的最有效的CDK2抑制剂。此外，通过将AZD5438局部递送到成年FVB小鼠，该化合物已显示满通过听觉脑干反应测量的顺铂诱导的耳毒性（ABR）阈值和人工耳蜗。 AZD5438也可以防止顺铂诱导的头发斑马鱼外侧线神经瘤的体内细胞损失在100 nm处。在这里，我们将评估复制抗癌小分子AZD5438的潜力口服生物利用的CDK2抑制剂已经被发现在健康的雄性中耐受在I期和II期临床试验中的志愿者和实心肿瘤患者，以防止顺铂引起的听力损失。我们的具体目的是测试AZD5438是否可以保护顺铂在小鼠模型中通过全身传递引起的听力损失。我们的方法是通过口服膨胀对用顺铂治疗的成年FVB小鼠进行AZD5438，测量其ABR 阈值并分析其人工耳蜗。口服AZD5438的最大无毒剂量将通过实验确定并测试听力保护作用。这项工作将丢掉在口服配方中使用AZD5438的可能性来对抗顺铂诱导的听力损失。与本地交付相比，口服有效药品的口服交付具有病人便利的优势。将来，我们还将测试口服的效率 AZD5438可保护与噪声和年龄相关的听力损失。如果口服AZD5438 在这项研究中保护保护性，我们将申请用于顺铂的SBIR II期研究癌症患者的听力损失。作为听力损失的CDK2抑制剂的主要发明者，两位Ting Therapeutics的创始人 LLC已经获得了AZD5438的独家专利权并提交了专利申请在欧洲，中国，日本和香港，正在谈判获得美国专利权的许可。 AZD5438的口头输送（如果成功）有可能向前迈出重要一步治疗癌症患者，以抵抗顺铂引起的听力损失。