CDK2 inhibitors for protecting hearing loss

标题：用于保护听力损失的CDK2抑制剂 项目总结 听力损失是我们社会的一个主要健康问题，影响着超过3.6亿人。 世界(世界卫生组织，2017年)。顺铂化疗导致永久性 在接受治疗的癌症患者中，听力损失的比例为40%-60%。到目前为止，还没有药物获得该委员会的批准 美国食品和药物管理局(FDA)对顺铂、噪声或年龄相关听力的保护 损失。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，因此这些化合物中的许多，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个独特化合物)，并鉴定为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……里面 下面重点筛选了另外187种具有理想药物样物的CDK2抑制剂 属性，我们确定AZD5438是最热门的，在耳蜗细胞中显示出540 nM的IC50 在顺铂处理的小鼠P3耳蜗外植体中，5 NM的体外IC50很高。 AZD5438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，通过给成年FVB小鼠局部注射AZD5438，该化合物显示出充分的 听性脑干反应检测对顺铂耳毒性的保护作用 (ABR)阈值和耳蜗学组织学。AZD5438对顺铂诱导的头发也有保护作用 100 nm下斑马鱼侧线神经肥大细胞的活体丢失。 在这里，我们将评估抗癌小分子AZD5438的潜在用途，一种 口服生物利用型CDK2抑制剂，已被发现在健康男性中可耐受 处于I期和II期临床试验的志愿者和实体瘤患者，以保护 顺铂所致听力损失。我们的具体目标是测试AZD5438是否可以防止 顺铂全身给药致小鼠听力损失模型。我们的方法是 AZD5438对顺铂处理的成年FVB小鼠灌胃给药，测定ABR 并对其耳蜗组织学进行分析。口服AZD5438的最大无毒剂量 将通过实验确定并测试听力保护效果。这项工作将脱颖而出 在口服制剂中使用AZD5438对抗顺铂诱导的可能性 听力损失。与本地递送相比，口服有效的药物递送 具有患者就诊方便的优点。今后，我们还将测试口服液的疗效 AZD5438，防止噪音和年龄相关的听力损失。如果口服AZD5438 在这项研究中证明具有保护作用，我们将申请顺铂的IND-Enabling SBIR第二阶段研究- 癌症患者的听力损失。 作为治疗听力损失的CDK2抑制剂的主要发明者，两人都是Ting Treeutics的创始人 有限责任公司已经获得了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，正在就授权美国专利权进行谈判。 如果AZD5438的口头传递成功，将有可能成为 治疗癌症患者顺铂所致的听力损失。

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.