CDK2 inhibitors for protecting hearing loss

用于保护听力损失的CDK2抑制剂 Ting Treateutics LLC是一家制药公司，开发预防和治疗听力损失的药物。 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%的患者出现高频听力损失。到目前为止，还没有药物获得食品和药物管理局的批准 保护顺铂所致听力损失的药物管理局。大多数候选化合物目前在 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 最近在一个耳蜗耳细胞系中进行了生物活性化合物的无偏高通量筛选，并 细胞周期蛋白依赖性激酶-2(CDK2)抑制剂是治疗顺铂的重要药物 细胞死亡和听力丧失。在这些化合物中，TT001是被测试的最有效的CDK2抑制剂。结果 从我们的SBIR I期试验中，证实口服TT001改善了顺铂引起的听力损失，但没有一般情况下 毒性。此外，TT001不干扰顺铂的体外抗癌活性。在这个SBIR第二阶段，我们将 新药启用实验验证TT001‘S对顺铂杀瘤效果的影响 并进行疗效研究，以确定最佳给药方案和治疗指数。长期的 TT001的目标是成为以顺铂为基础的治疗的标准耳保护药物。为此，我们将 在顺铂耳毒性小鼠模型中展示TT001‘S的疗效，该模型模仿给药方案 癌症患者(Aim1)。我们将测定血液中的药代动力学和药效学特征 外淋巴，以及对顺铂致聋豚鼠模型的疗效(目标2)。这一目标将是 根据与特纳科学研究机构签订的合同以及独立和信誉良好的合同执行 有限责任公司最后，我们将在小鼠体内验证TT001不干扰顺铂的抗癌活性 异种移植模型(目标3)。通过成功完成这些研究，Ting Treateutics将获得关键数据 启动研究性新药启用良好实验室实践投诉研究所必需的 和临床试验。Ting Treeutics LLC拥有使用CDK2抑制剂的独家国际权利 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 孔令辉。欧洲和中国的专利已经授予；美国、日本的类似专利申请正在申请中 (156803-2020年没有)，以及香港。Ting Treateutics正在与圣裘德儿童研究医院谈判 对于美国使用CDK2抑制剂治疗听力损失的专利权的方法(美国专利申请编号： 62/181,755；PCT/US16/38384；WO2016/205806)。这项提案的完成将使Ting Treeutics 就TT001的生产和许可事宜与制药公司展开对话。

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.