AZD5438-PROTAC: A selective CDK2 degrader that protects against cisplatin- and noise-induced hearing loss

Santanu Hati, Marisa Zallocchi, Robert Hazlitt, Yuju Li, Sarath Vijayakumar, Jaeki Min, Zoran Rankovic, Sándor Lovas, Jian Zuo

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number113849
JournalEuropean Journal of Medicinal Chemistry
Volume226
DOIs
StatePublished - Dec 15 2021

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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