Document text
Principal Investigator: Yunlong Huang
Organization: TING THERAPEUTICS, INC.
Fiscal Year: 2024
Award: $176,763
Funding agency: National Institute on Deafness and Other Communication Disorders
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.
Terms: <After Care><After-Treatment><Aftercare><Animal Model><Animal Models and Related Studies><Animals><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Antioxidants><Audiology><Auditory><Auditory Brainstem Responses><Award><Blood><Blood Reticuloendothelial System><CDDP><CDK2><CDK2 gene><Cancer Drug><Cancer Patient><Cancer Treatment><Cancer cell line><Cancers><Cavia><Cell Death Induction><Cell Division Kinase 2><Cell Line><CellLine><Chemicals><China><Cis-diammine-dichloroplatinum><Cis-diamminedichloridoplatinum><Cis-diamminedichloro Platinum (II)><Cis-dichloroammine Platinum (II)><Cis-platinous Diamine Dichloride><Cis-platinum II><Cis-platinum II Diamine Dichloride><Cisplatin><Cisplatina><Cisplatinum><Clinical><Clinical Evaluation><Clinical Testing><Clinical Treatment><Clinical Trials><Cochlea><Cochlear Organ><Contracting Opportunities><Contracts><Corti Cell><Cyclin-Dependent Kinase 2><Cysplatyna><Data><Detection><Development><Dichlorodiammineplatinum><Dose><Drug Kinetics><Drug usage><Drugs><Ear><Europe><Food and Drug Administration><Freedom><Future><Glutathione Metabolism><Glutathione Metabolism Pathway><Goals><Guinea Pigs><Guinea Pigs Mammals><HPLC><Hair Cells><Hearing Loss><Hearing Protection><High Frequency Deafness><High Performance Liquid Chromatography><High Pressure Liquid Chromatography><High Speed Liquid Chromatography><High Throughput Assay><High-Frequency Hearing Loss><Hong Kong><Hongkong><Human><Hypoacuses><Hypoacusis><Immunoblotting><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Internal Ear><International><Investigational Drugs><Investigational New Drugs><Japan><Knowledge><Labyrinth><Legal patent><Liberty><Licensing><Mainland China><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Testicular Neoplasm><Malignant Testicular Tumor><Malignant Tumor><Malignant Tumor of the Testis><Malignant neoplasm of testis><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measures><Mediation><Medication><Methods><Mice><Mice Mammals><Modern Man><Morphology><Murine><Mus><Negotiating><Negotiation><Neoplastic Disease Chemotherapeutic Agents><New Drug Approvals><Observation research><Observation study><Observational Study><Observational research><Oral><Outcome><PK/PD><Patents><Patients><Perilymph><Peyrone's Chloride><Peyrone's Salt><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacodynamics><Pharmacokinetics><Pharmacologic Substance><Pharmacological Substance><Phase><Phase I Study><Platinum Diamminodichloride><Procedures><Protocol><Protocols documentation><Publishing><QOL><Quality of life><Regimen><Research Contracts><Rights><Rodent Model><SBIR><Saint Jude><Saint Jude Children's Cancer Center><Saint Jude Children's Research Hospital><Small Business Innovation Research><Small Business Innovation Research Grant><Sodium Chloride><Sodium Hyposulfate><St. Jude><St. Jude Children's Cancer Center><St. Jude Children's Research Hospital><St. Jude Children's Research Hospital Comprehensive Cancer Center><St.Jude Children's Cancer Center><St.Jude Children's Research Hospital><St.Jude Children's Research Hospital Comprehensive Cancer Center><Strains Cell Lines><Testicular Cancer><Testing><Testis Cancer><Therapeutic><Therapeutic Index><Time><Toxic effect><Toxicities><Toxicology><Tumor Cell><Tumor-Specific Treatment Agents><USFDA><United States Food and Drug Administration><Western Blotting><Western Immunoblotting><Work><Xenograft Model><anti-cancer drug><anti-cancer therapy><anticancer activity><authority><cancer therapy><cancer-directed therapy><cis dichlorodiammineplatinum><cis platinum compound><cis-Diaminedichloroplatinum><cis-Diamminedichloroplatinum><cis-Diamminedichloroplatinum(II)><cis-Dichlorodiammineplatinum(II)><cis-Platinum><cisplatin associated hearing loss><cisplatin induced hearing deficit><cisplatin induced hearing impairment><cisplatin induced hearing loss><clinical test><commercial application><commercialization><cultured cell line><design><designing><developmental><drug induced hearing impairment><drug induced hearing loss><drug use><drug/agent><dysfunctional hearing><ear hair cell><efficacy study><experience><experiment><experimental research><experimental study><experiments><good laboratory practice><guinea pig model><healthy volunteer><hearing challenged><hearing defect><hearing deficient><hearing deficit><hearing difficulty><hearing dysfunction><hearing impairment><hearing loss prevention><hearing loss therapy><hearing loss treatment><hearing preservation><high throughput screening><in vitro activity><in vivo><inhibitor><inner ear><malignancy><manufacture><model of animal><mouse model><murine model><neoplasm/cancer><neoplastic cell><otoacoustic emission><otoprotectant><otoprotective><ototoxic><ototoxicity><pharmaceutical><pharmacokinetics and pharmacodynamics><pharmacologic><phase 1 study><post treatment><pre-clinical trial><preclinical trial><preserve hearing><prevent><prevent hearing loss><preventing><protect hearing><protein blotting><research clinical testing><safety and feasibility><salt><sodium hyposulfite><sodium thiosulfate><technological innovation><treatment for hearing loss><trial regimen><trial treatment><tumor><tumor xenograft><vitamin metabolism><webinar><xenograft transplant model><xenotransplant model>