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：CDK2抑制剂保护听力损失项目概要听力损失是我们社会的一个主要健康问题，影响超过 3.6 亿人全球范围内（世界卫生组织，2017）。迄今为止，40-60% 接受治疗的癌症患者出现听力损失，尚未批准任何药物。美国食品和药物管理局 (FDA) 用于保护顺铂、噪音或年龄相关的听力目前处于临床前试验的大多数候选化合物都与抗氧化剂有关，维生素和谷胱甘肽代谢，以及许多这些化合物，例如钠硫代硫酸盐会干扰顺铂杀死肿瘤细胞的能力。我们最近对生物活性（以下化合物）进行了无偏见的高通量筛选：耳蜗细胞系中的 4,385 种独特化合物）并鉴定出细胞周期蛋白依赖性激酶 2 （CDK2）作为顺铂诱导的细胞死亡和听力损失的重要治疗靶点。以下重点筛选了另外 187 种具有理想药物样作用的 CDK2 抑制剂性质，我们确定 AZD5438 为热门产品，在耳蜗细胞中的 IC50 为 540 nM 在用顺铂处理的小鼠 P3 耳蜗外植体中，离体 IC50 为 5 nM。 AZD5438 是我们的耳蜗外植体研究中测试的最有效的 CDK2 抑制剂。此外，通过将 AZD5438 局部递送至成年 FVB 小鼠，该化合物显示出充分的通过听觉脑干反应测量对顺铂引起的耳毒性的保护 (ABR) 阈值和耳蜗组织学也能防止顺铂诱导的毛发。 100 nM 斑马鱼侧线神经丘体内细胞损失。在这里，我们将评估重新利用抗癌小分子 AZD5438 的潜力，AZD5438 是一种口服生物可利用的 CDK2 抑制剂，已被发现在健康男性中具有耐受性志愿者和实体瘤患者进行 I 期和 II 期临床试验，以预防我们的具体目标是测试 AZD5438 是否可以预防顺铂引起的听力损失。我们的方法是通过在小鼠模型中全身递送顺铂引起的听力损失。通过口服管饲法给用顺铂治疗的成年 FVB 小鼠施用 AZD5438，测量其 ABR 阈值并分析其耳蜗组织学口服AZD5438的最大无毒剂量。将通过实验确定和测试这项工作的听力保护效果。阐明在口服制剂中使用 AZD5438 对抗顺铂诱导的可能性与局部给药相比，口服给药有效。优点是方便患者，以后我们也会测试口服的疗效。 AZD5438 可预防与噪音和年龄相关的听力损失如果口服 AZD5438。在本研究中证明具有保护性，我们将申请顺铂的 IND 启用 SBIR II 期研究导致癌症患者听力损失。作为治疗听力损失的CDK2抑制剂的主要发明者，Ting Therapeutics的两位创始人 LLC已获得AZD5438的独家专利权并已提交专利申请在欧洲、中国、日本和香港，并正在谈判获得美国专利权的许可。 AZD5438 的口服给药如果成功的话，有可能向前迈出重要一步。治疗癌症患者因顺铂引起的听力损失。