CDK2 inhibitors for protecting hearing loss

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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.