azd5438 and Hearing-Loss--Noise-Induced

Cyclin-dependent kinase 2 (CDK2) is a potential therapeutic target for the treatment of hearing loss and cancer. Previously, we identified AZD5438 and AT7519-7 as potent inhibitors of CDK2, however, they also targeted additional kinases, leading to unwanted toxicities. Proteolysis Targeting Chimeras (PROTACs) are a new promising class of small molecules that can effectively direct specific proteins to proteasomal degradation. Herein we report the design, synthesis, and characterization of PROTACs of AT7519-7 and AZD5438 and the identification of PROTAC-8, an AZD5438-PROTAC, that exhibits selective, partial CDK2 degradation. Furthermore, PROTAC-8 protects against cisplatin ototoxicity and kainic acid excitotoxicity in zebrafish. Molecular dynamics simulations reveal the structural requirements for CDK2 degradation. Together, PROTAC-8 is among the first-in-class PROTACs with in vivo therapeutic activities and represents a new lead compound that can be further developed for better efficacy and selectivity for CDK2 degradation against hearing loss and cancer.

Topics: Animals; Antineoplastic Agents; Cell Line; Cisplatin; Cyclin-Dependent Kinase 2; Dose-Response Relationship, Drug; Hearing Loss, Noise-Induced; Humans; Imidazoles; Molecular Dynamics Simulation; Molecular Structure; Protective Agents; Protein Kinase Inhibitors; Pyrimidines; Structure-Activity Relationship; Zebrafish