CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss

• DOI: 10.1084/jem.20172246
• Publication Date: 2018-03-07T12:25:21Z
• Authors: Tal Teitz; Jie Fang; Asli N. Goktug; Justine D. Bonga; Shiyong Diao; Robert A. Hazlitt; Luigi Iconaru; Marie Morfouace; Duane Currier; Yinmei Zhou; Robyn A. Umans; Michael R. Taylor; Cheng Cheng; Jaeki Min; Burgess Freeman; Junmin Peng; Martine F. Roussel; Richard Kriwacki; R. Kiplin Guy; Taosheng Chen; Jian Zuo
• Keywords: Mice, Knockout; 0301 basic medicine; Indoles; Cell Death; Cyclin-Dependent Kinase 2; Drug Resistance; Benzazepines; Lateral Line System; Mitochondria; Rats; 3. Good health; Mice, Inbred C57BL; Small Molecule Libraries; 03 medical and health sciences; Germ Cells; Hearing Loss, Noise-Induced; Cytoprotection; Cell Line, Tumor; Hair Cells, Auditory; Animals; Cisplatin; Reactive Oxygen Species; Protein Kinase Inhibitors; Research Articles

Hearing loss caused by aging, noise, cisplatin toxicity, or other insults affects 360 million people worldwide, but there are no Food and Drug Administration–approved drugs to prevent or treat it. We screened 4,385 small molecules in a cochlear cell line and identified 10 compounds that protected against cisplatin toxicity in mouse cochlear explants. Among them, kenpaullone, an inhibitor of multiple kinases, including cyclin-dependent kinase 2 (CDK2), protected zebrafish lateral-line neuromasts from cisplatin toxicity and, when delivered locally, protected adult mice and rats against cisplatin- and noise-induced hearing loss. CDK2-deficient mice displayed enhanced resistance to cisplatin toxicity in cochlear explants and to cisplatin- and noise-induced hearing loss in vivo. Mechanistically, we showed that kenpaullone directly inhibits CDK2 kinase activity and reduces cisplatin-induced mitochondrial production of reactive oxygen species, thereby enhancing cell survival. Our experiments have revealed the proapoptotic function of CDK2 in postmitotic cochlear cells and have identified promising therapeutics for preventing hearing loss.