2. Academic Validation
  3. Discovery of WWZ-11-098: a rigid and selective CDK6 degrader

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

  • Eur J Med Chem. 2026 Mar 5:305:118569. doi: 10.1016/j.ejmech.2026.118569.
Wanwan Zhang 1,  Jinfeng Wen 1,  Yuanyuan Wu 1,  Yong Xuan 1,  Qiangqiang Han 2,  Xi Chen 2,  Jingtian Yu 3,  Haijun Yu 4,  Baishan Jiang 5
Affiliations

Affiliations

  • 1 Department of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China.
  • 2 SpecAlly Life Technology Co., Ltd., Wuhan, Hubei, 430075, China.
  • 3 Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China. Electronic address: jingtian_yu@whu.edu.cn.
  • 4 Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China. Electronic address: haijunyu@whu.edu.cn.
  • 5 Department of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China; Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China. Electronic address: baishan_jiang@whu.edu.cn.
PMID: 41548292 DOI: 10.1016/j.ejmech.2026.118569
Abstract

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.

Keywords

CDK2/4/6 inhibitor; CDK6 degrader; Cell cycle; Cereblon.

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