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

• Published in: European journal of medicinal chemistry Vol. 226; p. 113849
• Main Authors: Hati, Santanu, Zallocchi, Marisa, Hazlitt, Robert, Li, Yuju, Vijayakumar, Sarath, Min, Jaeki, Rankovic, Zoran, Lovas, Sándor, Zuo, Jian
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.12.2021; Elsevier
• Subjects: Animals; Antineoplastic Agents - pharmacology; CDK2-Proteolysis; Cell Line; Chemistry, Medicinal; Cisplatin - antagonists & inhibitors; Cisplatin - pharmacology; Cisplatin-induced hearing loss; Cyclin-Dependent Kinase 2 - antagonists & inhibitors; Cyclin-Dependent Kinase 2 - metabolism; Dose-Response Relationship, Drug; Hearing Loss, Noise-Induced - drug therapy; Hearing Loss, Noise-Induced - metabolism; Humans; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Life Sciences & Biomedicine; Molecular Dynamics Simulation; Molecular Structure; Noise-induced hearing loss; Pharmacology & Pharmacy; PROTAC; Protective Agents - chemical synthesis; Protective Agents - chemistry; Protective Agents - pharmacology; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Science & Technology; Structure-Activity Relationship; Zebrafish; AML; FDA; CRBN; PROTAC; HEI-OC1; CDK; CDK9; CDK2-Proteolysis; Cisplatin-induced hearing loss; CDK7; FVB; STS; CDK5; DCCM; Noise-induced hearing loss; CDK2; IC50; MD; CDK1; VHL; TARGET; RECOGNITION; SODIUM THIOSULFATE; PROLIFERATION; PROTACS; KINASE-INHIBITOR AZD5438; E3 UBIQUITIN LIGASES; CHILDREN; TOLERABILITY; DEGRADATION
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113849

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. [Display omitted] •PROTAC-based hearing loss therapy.•In vivo CDK2 degradation.•Prevention of hair cell damage.