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

Area of Science:

• Biochemistry
• Pharmacology
• Molecular Biology

Background:

• Cyclin-dependent kinase 2 (CDK2) is implicated in hearing loss and cancer.
• Existing CDK2 inhibitors like AZD5438 and AT7519-7 cause off-target toxicities.
• Proteolysis Targeting Chimeras (PROTACs) offer a novel approach for targeted protein degradation.

Purpose of the Study:

• To design, synthesize, and characterize PROTACs targeting CDK2 using AZD5438 and AT7519-7 as warheads.
• To identify a PROTAC with selective CDK2 degradation and therapeutic potential.
• To investigate the structural basis of CDK2 degradation via molecular dynamics.

Main Methods:

• Synthesis and characterization of novel PROTAC molecules.
• Assessment of CDK2 degradation selectivity and potency.
• Evaluation of PROTAC efficacy in zebrafish models of ototoxicity (cisplatin) and excitotoxicity (kainic acid).
• Molecular dynamics simulations to elucidate degradation mechanisms.

Main Results:

• Identification of PROTAC-8, an AZD5438-based PROTAC, achieving selective, partial CDK2 degradation.
• PROTAC-8 demonstrated therapeutic effects by protecting against cisplatin-induced ototoxicity and kainic acid-induced excitotoxicity in vivo.
• Molecular dynamics simulations provided insights into the structural requirements for effective CDK2 degradation.

Conclusions:

• PROTAC-8 represents a first-in-class molecule with demonstrated in vivo therapeutic activity via targeted CDK2 degradation.
• This PROTAC is a promising lead compound for developing treatments for hearing loss and cancer.
• Further optimization for enhanced efficacy and selectivity is warranted.