Development of Dual and Selective Degraders of Cyclin-Dependent Kinases 4 and 6

Area of Science:

• Molecular Biology
• Oncology
• Drug Discovery

Background:

• Cyclin-dependent kinases 4 and 6 (CDK4/6) are crucial cell cycle regulators.
• Existing FDA-approved CDK4/6 inhibitors treat metastatic breast cancer.
• Selective CDK4/6 targeting is challenging due to conserved ATP-binding sites.

Purpose of the Study:

• To develop novel imide-based degrader molecules targeting CDK4/6.
• To achieve selective degradation of CDK4, CDK6, or both.
• To investigate the therapeutic potential of combined degradation of CDK4/6 and IKZF1/3.

Main Methods:

• Design and synthesis of imide-based small molecules.
• Assessment of degradation activity against CDK4, CDK6, IKZF1, and IKZF3.
• Evaluation of anti-proliferative effects in mantle cell lymphoma cell lines.

Main Results:

• Developed imide-based molecules capable of dual or selective CDK4/6 degradation.
• Demonstrated tunable activity against IKZF1 and IKZF3.
• Observed enhanced anti-proliferative effects in mantle cell lymphoma with combined IKZF1/3 and CDK4/6 degradation.

Conclusions:

• Reported the first compounds for selective CDK4 and CDK6 degradation.
• These molecules serve as tools to study distinct biological functions of CDK4 and CDK6.
• Combined degradation strategy shows promise for enhanced anti-cancer activity.