TY - JOUR
T1 - AZD5438-PROTAC
T2 - A selective CDK2 degrader that protects against cisplatin- and noise-induced hearing loss
AU - Hati, Santanu
AU - Zallocchi, Marisa
AU - Hazlitt, Robert
AU - Li, Yuju
AU - Vijayakumar, Sarath
AU - Min, Jaeki
AU - Rankovic, Zoran
AU - Lovas, Sándor
AU - Zuo, Jian
N1 - Funding Information:
We thank the Zuo lab members for their critical comments on the study. The study is supported in part by NIH-R01DC015444, NIH-R01DC015010, USAMRMC-RH170030, ONR-N00014-18-1-2507, DoD-RH190050, LB692/Creighton, 1P20GM139762-01, ALSAC, P30CA21765, and the Bellucci Foundation.
Funding Information:
We thank the Zuo lab members for their critical comments on the study. The study is supported in part by NIH - R01DC015444 , NIH - R01DC015010 , USAMRMC - RH170030 , ONR - N00014-18-1-2507 , DoD - RH190050 , LB692 / Creighton , 1P20GM139762-01 , ALSAC , P30CA21765 , and the Bellucci Foundation .
Publisher Copyright:
© 2021 Elsevier Masson SAS
PY - 2021/12/15
Y1 - 2021/12/15
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ejmech.2021.113849
DO - 10.1016/j.ejmech.2021.113849
M3 - Article
AN - SCOPUS:85115800637
VL - 226
JO - CHIM.THER.
JF - CHIM.THER.
SN - 0223-5234
M1 - 113849
ER -