CDK2 inhibitors for protecting hearing loss

用于保护听力损失的CDK 2抑制剂 Ting Therapeutics LLC是一家开发预防和治疗听力损失药物的制药公司。 顺铂是治疗癌症最广泛使用的药物之一。然而，顺铂抗癌治疗导致 40-60%的患者患有高频听力损失。到目前为止，食品和药物管理局还没有批准任何药物， 预防顺铂引起的听力损失的药物管理。目前，大多数候选化合物 临床前和临床试验与抗氧化剂、维生素和谷胱甘肽代谢有关，因此许多 这些化合物，如硫代硫酸钠，可以干扰顺铂杀死肿瘤细胞的能力。我们 最近在耳蜗细胞系中进行了生物活性化合物的无偏高通量筛选， 确定细胞周期蛋白依赖性激酶-2（CDK 2）抑制剂作为顺铂诱导的 细胞死亡和听力损失。在这些化合物中，TT 001是测试的最有效的CDK 2抑制剂。结果 从我们的SBIR第一阶段，证明口服TT 001改善顺铂诱导的听力损失，没有一般的 毒性此外，TT 001不干扰顺铂的体外抗癌活性。在SBIR第二阶段，我们将 进行研究性新药使能实验，以测试TT 001对顺铂的肿瘤杀伤效力的影响 并进行功效研究以确定最佳给药方案和治疗指数。长期 目标是使TT 001成为基于顺铂的治疗的标准耳保护药物。为此，我们将 证明了TT 001在顺铂耳毒性小鼠模型中的疗效，该模型模拟了 癌症患者（Aim 1）。我们将确定血液中的药代动力学和药效学特征， 外淋巴液，以及疗效，在豚鼠模型顺铂诱导的听力损失（目的2）。这一目标将是 根据与独立且信誉良好的合同研究组织Turner Scientific签订的合同进行 LLC.最后，我们将验证TT 001在小鼠体内不干扰顺铂的抗癌活性 模型异种移植物（Aim 3）。通过成功完成这些研究，汀治疗将获得关键数据 启动新药研究质量管理规范投诉研究所需的 和临床试验。Ting Therapeutics LLC拥有CDK 2抑制剂的国际独家使用权， 听力损失的治疗该公司已在日本、欧洲、中国和香港申请了国际专利 Kong.已在欧洲和中国获得专利;美国、日本正在申请类似专利 (No 2020-156803）和香港。Ting Therapeutics正在与圣裘德儿童研究医院进行谈判 用于听力损失的CDK 2抑制剂的美国使用方法专利权（美国专利申请No. 62/181，755; PCT/US16/38384; WO 2016/205806）。该提案的完成将使汀治疗 与制药公司就TT 001的生产和许可展开对话。

CDK2 inhibitors for protecting hearing loss Ting Therapeutics LLC is a pharmaceutical company developing drugs to prevent and treat hearing loss. Cisplatin is one of the most widely used drugs to treat cancers. However cisplatin anticancer therapy causes high frequency hearing loss in 40-60% of the patients. To date, no drugs have been approved by the Food and Drug Administration for protection from cisplatin-induced hearing loss. Most candidate compounds currently in pre-clinical and 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 in a cochlear ear cell line and identified cyclin dependent kinase-2 (CDK2) inhibitors as important therapeutic compounds for cisplatin-induced cell death and hearing loss. Among those compounds, TT001 was the most potent CDK2 inhibitor tested. Results from our SBIR Phase I, demonstrated that oral TT001 ameliorated cisplatin-induced hearing loss with no general toxicity. Moreover, TT001 did not interfere with cisplatin anti-cancer activity in vitro. In this SBIR Phase II, we will perform Investigational New Drug-enabling experiments to test TT001’s effect on cisplatin’s tumor killing efficacy in vivo and to conduct efficacy studies to define an optimal dosing regimen and therapeutic index. The long-term goal is for TT001 to become a standard otoprotective drug of cisplatin-based therapies. For this purpose, we will demonstrate TT001’s efficacy in a mouse model of cisplatin ototoxicity that mimics the administration protocol in cancer patients (Aim1). We will determine pharmacokinetics and pharmacodynamics profiles in blood and perilymph, as well as efficacy, in a guinea pig model for cisplatin-induced hearing loss (Aim 2). This Aim will be performed under contract with and independent and reputable Contract Research Organization, Turner Scientific LLC. Finally, we will verify that TT001 does not interfere with cisplatin’s anti-cancer activity in vivo in mouse model xenografts (Aim 3). By successfully completing these studies, Ting Therapeutics will obtain critical data necessary for the initiation of Investigational New Drug-enabling Good Laboratory Practice complaint studies and clinical trials. Ting Therapeutics LLC has the exclusive international rights for the use of CDK2 inhibitors in the treatment of hearing loss. The company has filed for international patents in Japan, Europe, China and Hong Kong. The patent in Europe and China has been awarded; similar patent applications are pending in US, Japan (No 2020-156803), and Hong Kong. Ting Therapeutics is negotiating with St. Jude Children’s Research Hospital for the US Method of Use patent rights on CDK2 inhibitors for hearing loss (US Patent Application No. 62/181,755; PCT/US16/38384; WO 2016/205806). The completion of this proposal will allow Ting Therapeutics to initiate conversations with pharmaceutical companies for the manufacturing and licensing of TT001.