CDK2 inhibitors for protecting hearing loss

CDK2 抑制剂可保护听力损失

基本信息

批准号：
10520065
负责人：
Yunlong Huang
金额：
$ 54.13万
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 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10520065
关键词：
Aftercare Animal Model Animals Antineoplastic Agents Antioxidants Audiology Auditory Auditory Brainstem Responses Authorization documentation Award Blood CDK2 gene Cancer Patient Cancer cell line Cavia Cell Death Induction Cell Line Chemicals China Cisplatin Clinical Clinical Treatment Clinical Trials Cochlea Contracts Data Detection Development Dose Drug Kinetics Drug usage Ear Europe Freedom Future Glutathione Metabolism Pathway Goals Hair Cells Hearing Protection High Pressure Liquid Chromatography High-Frequency Hearing Loss Hong Kong Human Immunohistochemistry International Investigational Drugs Japan Knowledge Labyrinth Legal patent Licensing Malignant Neoplasms Malignant neoplasm of testis Mass Spectrum Analysis Measures Mediation Methods Morphology Mus New Drug Approvals Observational Study Oral Outcome Patients Perilymph Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phase Procedures Protocols documentation Publishing Quality of life Regimen Research Contracts Rights Rodent Model Saint Jude Children&apos s Research Hospital Small Business Innovation Research Grant Sodium Chloride Testing Therapeutic Therapeutic Index Time Toxic effect Toxicology United States Food and Drug Administration Western Blotting Work Xenograft Model anticancer activity authority cancer therapy cisplatin induced hearing loss commercial application commercialization design efficacy study experience experimental study good laboratory practice guinea pig model healthy volunteer hearing impairment hearing loss treatment hearing preservation high throughput screening in vitro activity in vivo inhibitor manufacture mouse model neoplastic cell otoacoustic emission otoprotectant ototoxicity pharmacokinetics and pharmacodynamics pharmacologic phase 1 study preclinical trial prevent prevent hearing loss research clinical testing safety and feasibility sodium thiosulfate technological innovation tumor tumor xenograft vitamin metabolism webinar

项目摘要

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.

保护听力损失的CDK2抑制剂 Ting Therapeutics LLC是一家制药公司，开发用于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。但是顺铂抗癌治疗原因 40-60％的患者的高频听力损失。迄今为止，尚未获得食物批准的药物和药物管理药物治疗以外铂诱导的听力损失。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（例如硫代硫酸钠）可以干扰顺铂杀死肿瘤细胞的能力。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，鉴定的细胞周期蛋白依赖性激酶-2（CDK2）抑制剂是顺铂诱导的重要治疗化合物细胞死亡和听力损失。在这些化合物中，TT001是测试的最潜在的CDK2抑制剂。结果从我们的SBIR I期开始，表明口服TT001改善了顺铂引起的听力损失，没有一般毒性。此外，TT001在体外不会干扰顺铂抗癌活性。在SBIR第二阶段中，我们将执行研究性新药实验，以测试TT001对顺铂的肿瘤杀伤有效性的影响体内并进行效率研究以定义最佳的给药方案和治疗指数。长期目标是使TT001成为基于顺铂的疗法的标准眼药物。为此，我们将演示TT001的效率在鼠标的鼠标模型中，该模型模仿了管理方案癌症患者（AIM1）。我们将确定血液中的药代动力学和药效学特征在豚鼠模型中，以顺铂诱导的听力损失（AIM 2）中，围绕perilymph以及有效。这个目标将是根据与独立和信誉良好的合同研究组织合同进行的特纳科学 LLC。最后，我们将验证TT001不会干扰鼠标中的顺铂的抗癌活性模型Xenographics（AIM 3）。通过成功完成这些研究，Ting Therapeutics将获得关键数据为了调查新药的良好实验室实践投诉研究所必需的和临床试验。 Ting Therapeutics LLC拥有使用CDK2抑制剂的独家国际权利听力损失的治疗。该公司已申请日本，欧洲，中国和洪的国际专利孔。欧洲和中国的专利已获得授予；日本美国正在等待类似的专利申请（第2020-156803号）和香港。 Ting Therapeutics正在与圣裘德儿童研究医院进行谈判用于美国在CDK2抑制剂上使用专利权的方法（美国专利申请号） 62/181,755; PCT/US16/38384; WO 2016/205806）。该提案的完成将允许治疗学与制药公司发起对TT001制造和许可的对话。