CDK2 inhibitors for protecting hearing loss

CDK2 抑制剂可保护听力损失

• 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
• 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

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：用于保护听力损失的CDK 2抑制剂 项目摘要 听力损失是我们社会中的一个主要健康问题，影响着超过3.6亿人 （世界卫生组织，2017）。顺铂化疗导致永久性 40 - 60%接受治疗的癌症患者有听力损失。到目前为止，还没有药物被批准的 美国食品药品监督管理局（FDA）的保护顺铂，噪音，或年龄相关的听力 损失目前在临床前试验中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，因此许多这些化合物，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筛选（总共 4，385种独特的化合物），并鉴定了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。在 以下对另外187种CDK2抑制剂的集中筛选， 根据这些特性，我们确定AZD 5438为最佳选择，在耳蜗细胞中显示出540 nM的IC50 在用顺铂处理的小鼠P3耳蜗外植体中， AZD 5438是在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AZD 5438局部递送至成年FVB小鼠，化合物显示出完全的 通过听觉脑干反应测定对顺铂诱导的耳毒性的保护作用 (ABR)阈值和耳蜗组织学。AZD 5438也可保护顺铂诱导的毛发 在100 nM下，斑马鱼侧线神经瘤中的体内细胞损失。 在这里，我们将评估重新利用抗癌小分子AZD 5438的潜力， 已发现在健康男性中耐受的口服生物可利用的CDK2抑制剂 I期和II期临床试验中的志愿者和实体瘤患者， 顺铂引起的听力损失我们的具体目标是测试AZD5438是否能保护 在小鼠模型中通过全身递送顺铂诱导的听力损失。我们的做法是 经口灌胃给予顺铂处理的成年FVB小鼠AZD 5438，测量其ABR 阈值并分析其耳蜗组织学。口服AZD 5438的最大无毒剂量 将通过实验确定并测试听力保护效果。这项工作将摆脱 阐明了在口服制剂中使用AZD 5438对抗顺铂诱导的 听力损失与局部递送相比，口服递送有效的药物产品 具有方便患者的优点。今后，我们还将测试口服 AZD5438可防止噪音和年龄相关的听力损失。如果口服AZD 5438 在这项研究中证明了保护性，我们将申请顺铂的IND使能SBIR II期研究， 导致癌症患者听力损失。 作为CDK2抑制剂治疗听力损失的主要发明者，Ting Therapeutics的两位创始人 LLC已获得AZD5438的独家专利权并提交专利申请 在欧洲，中国，日本和香港，并正在谈判许可美国专利权。 AZD 5438的口服给药如果成功，有可能成为向前迈出的重要一步 治疗癌症患者顺铂引起的听力损失。