Discovery of small molecule degraders for modulating cell cycle

Area of Science:

• Molecular Biology
• Biochemistry
• Drug Discovery

Background:

• The cell cycle is a tightly regulated process essential for cell division, involving proteins like cyclin-dependent kinases (CDKs) and cyclins.
• Dysregulation of these cell cycle regulators is implicated in various diseases, including cancer.
• Traditional inhibition strategies have limitations in targeting both enzymatic and scaffold functions.

Purpose of the Study:

• To provide a comprehensive summary of recent advancements in targeted protein degraders for CDKs and cyclins.
• To overview the selectivity, applications, and validation of existing CDK degraders.
• To discuss strategies for developing degraders for CDK members currently lacking them.

Main Methods:

• Review of recent scientific literature on proteolysis-targeting chimeras (PROTACs) and molecular glues targeting CDKs and cyclins.
• Analysis of the selectivity, application, and validation data for developed CDK degraders.
• Discussion of potential future directions and methodologies for novel degrader development.

Main Results:

• PROTACs and molecular glues represent a novel approach to eliminate both enzymatic and scaffold functions of CDKs and cyclins.
• Significant progress has been made in developing selective degraders for various CDKs.
• The field is rapidly evolving, with ongoing research into new degrader designs and applications.

Conclusions:

• Targeted protein degradation via PROTACs and molecular glues offers a promising therapeutic strategy for diseases driven by cell cycle dysregulation.
• Further research is needed to develop degraders for all CDK family members and to optimize their clinical application.
• This review highlights the dynamic progress and future potential of CDK and cyclin protein degraders in biomedical research.