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- W3199626449 abstract "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." @default.
- W3199626449 created "2021-09-27" @default.
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- W3199626449 date "2021-12-01" @default.
- W3199626449 modified "2023-10-10" @default.
- W3199626449 title "AZD5438-PROTAC: A selective CDK2 degrader that protects against cisplatin- and noise-induced hearing loss" @default.
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- W3199626449 doi "https://doi.org/10.1016/j.ejmech.2021.113849" @default.
- W3199626449 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/8608744" @default.
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