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

Dysregulation of the cell cycle, a hallmark of cancer, frequently involves aberrant activation of cyclin D-CDK4/6 complexes. Although dual-CDK4/6 inhibitors are effective in advanced hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer, CDK6 is preferentially expressed and functionally upregulated in hematologic malignancies, making it a promising therapeutic target. The high structural homology between CDK4 and CDK6, however, has made developing selective CDK6 inhibitors exceptionally difficult. Herein, we report the design and synthesis of a novel series of CDK6 degraders based on a CDK2/4/6 inhibitor. This investigation led to the discovery of a CDK6 degrader WWZ-11-098. WWZ-11-098 induced pronounced CDK6 degradation (DC50 = 2.6 nM and Dmax >99 %) in a Cereblon (CRBN)-dependent manner, while sparing CDK1, CDK2, CDK4, and CDK9. Moreover, WWZ-11-098 exhibited potent antiproliferation activity (MOLT-4: IC50 = 70 nM) by inducing G1-S cell cycle arrest. In addition, WWZ-11-098 displayed favorable pharmacokinetic properties (Cmax = 11833 ng/mL, T1/2 = 2.64 h after a 5 mpk IV dose) and exhibited robust antitumor efficacy (TGI: 77.1 % @10 mpk) in a MOLT-4 xenograft model without signs of toxicity. The compound provides not only a valuable chemical probe but also a lead structure for further development of CDK6 degraders.