期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 226, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2021.113849
关键词
CDK2-Proteolysis; PROTAC; Cisplatin-induced hearing loss; Noise-induced hearing loss
资金
- ALSAC [P30CA21765]
- Bellucci Foundation
- [NIH-R01DC015444]
- [NIH-R01DC015010]
- [USAMRMC-RH170030]
- [ONR-N00014-18-12507]
- [DoD-RH190050]
- [LB692/Creighton]
- [1P20GM139762-01]
This study introduced a new class of small molecules called PROTACs that can effectively degrade the CDK2 protein, with PROTAC-8 showing potential therapeutic activities. Experimental results demonstrated that PROTAC-8 can protect zebrafish from drug-induced auditory and neurotoxicity, indicating its promising role in treating hearing loss and cancer.
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. (C) 2021 Elsevier Masson SAS. All rights reserved.
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