Discovery of WWZ-11-098: a rigid and selective CDK6 degrader

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• Cell cycle dysregulation is a cancer hallmark, often involving cyclin D-CDK4/6 complexes.
• While CDK4/6 inhibitors work for breast cancer, CDK6 is a key target in hematologic malignancies.
• Developing selective CDK6 inhibitors is challenging due to structural similarity with CDK4.

Purpose of the Study:

• To design and synthesize novel CDK6 degraders.
• To discover a potent and selective CDK6 degrader for potential therapeutic applications.
• To evaluate the preclinical efficacy and pharmacokinetic properties of a lead compound.

Main Methods:

• Design and synthesis of CDK6 degraders based on a CDK2/4/6 inhibitor scaffold.
• Assessment of compound-induced CDK6 degradation in a Cereblon (CRBN)-dependent manner.
• Evaluation of antiproliferation activity, cell cycle arrest, pharmacokinetics, and in vivo antitumor efficacy in a xenograft model.

Main Results:

• Discovery of WWZ-11-098, a potent CDK6 degrader (DC50 = 2.6 nM, Dmax >99%) sparing other CDKs.
• WWZ-11-098 demonstrated significant antiproliferation activity (IC50 = 70 nM) via G1-S cell cycle arrest.
• The compound exhibited favorable pharmacokinetics and robust antitumor efficacy (77.1% TGI) in a MOLT-4 xenograft model without toxicity.

Conclusions:

• WWZ-11-098 is a highly effective and selective CDK6 degrader.
• The compound shows promise as a chemical probe and a lead structure for developing new cancer therapies.
• Targeting CDK6 degradation offers a viable strategy for treating hematologic malignancies.