CDK2 inhibitors for protecting hearing loss

CDK2 抑制剂可保护听力损失

基本信息

批准号：
10382178
负责人：
Marisa L. Zallocchi
金额：
$ 56.62万
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/10382178
关键词：
Aftercare Animal Model Animals Antineoplastic Agents Antioxidants Auditory Auditory Brainstem Responses Award Blood CDK2 gene Cancer Patient Cancer cell line Cavia Cell Death 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 Pharmacology Phase Procedures Protocols documentation Publishing Quality of life Regimen Research Contracts Rights Rodent Model Saint Jude Children&apos s Research Hospital Ships Small Business Innovation Research Grant Sodium Chloride Testing Therapeutic Therapeutic Index Time Toxic effect Toxicology United States Food and Drug Administration Work Xenograft Model anticancer activity authority base 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 mouse model neoplastic cell otoacoustic emission otoprotectant ototoxicity pharmacokinetics and pharmacodynamics 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.

CDK2 抑制剂可保护听力损失 Ting Therapeutics LLC 是一家开发预防和治疗听力损失药物的制药公司。顺铂是最广泛使用的治疗癌症的药物之一，然而顺铂抗癌治疗会引起癌症。 40-60% 的患者患有高频听力损失迄今为止，食品和药物管理局尚未批准任何药物。目前大多数候选化合物都在药物管理局的保护中，以防止顺铂引起的听力损失。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。最近对耳蜗细胞系中的生物活性化合物进行了公正的高通量筛选，确定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在这些化合物中，TT001 是最有效的 CDK2 抑制剂。来自我们的 SBIR 第一阶段的研究表明，口服 TT001 可以改善顺铂引起的听力损失，并且没有一般性影响此外，TT001 不会干扰顺铂的体外抗癌活性。进行研究性新药启用实验，以测试 TT001 对顺铂的肿瘤杀伤功效的影响体内并进行最佳疗效研究以确定给药方案和长期治疗指数。我们的目标是让 TT001 成为顺铂疗法的标准耳保护药物。证明 TT001 在顺铂耳毒性小鼠模型中的功效，该模型模仿了中的给药方案我们将确定血液和癌症患者的药代动力学和药效学特征。顺铂引起的听力损失的豚鼠模型中的外淋巴以及功效（目标 2）。根据与独立且信誉良好的合同研究组织特纳科学公司签订的合同进行最后，我们将在小鼠体内验证TT001不会干扰顺铂的抗癌活性。通过成功完成这些研究，Ting Therapeutics 将获得关键数据。启动研究性新药良好实验室规范投诉研究所必需的 Ting Therapeutics LLC 拥有在以下领域使用 CDK2 抑制剂的独家国际权利。该公司已在日本、欧洲、中国和香港申请了国际专利。欧洲和中国已获得专利；美国、日本正在申请类似专利。（编号 2020-156803），香港 Ting Therapeutics 正在与 St. Jude 儿童研究医院进行谈判。用于治疗听力损失的 CDK2 抑制剂的美国使用方法专利权（美国专利申请号： 62/181,755；PCT/US16/38384；WO 2016/205806）。与制药公司就 TT001 的生产和许可展开对话。