2. Academic Validation
  3. Discovery of a first-in-class CDK2 selective degrader for AML differentiation therapy

Discovery of a first-in-class CDK2 selective degrader for AML differentiation therapy

  • Nat Chem Biol. 2021 May;17(5):567-575. doi: 10.1038/s41589-021-00742-5.
Liguo Wang  # 1,  Xuejing Shao  # 2,  Tianbai Zhong  # 3,  Yue Wu  # 1,  Aixiao Xu  # 2,  Xiuyun Sun 1,  Hongying Gao 1,  Yongbo Liu 1,  Tianlong Lan 1,  Yan Tong 1,  Xue Tao 4,  Wenxin Du 2,  Wei Wang 2,  Yingqian Chen 2,  Ting Li 5 6,  Xianbin Meng 6,  Haiteng Deng 5 6,  Bo Yang 2,  Qiaojun He 2,  Meidan Ying 7,  Yu Rao 8 9
Affiliations

Affiliations

  • 1 MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, China.
  • 2 Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
  • 3 Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
  • 4 Department of Research, Beijing Rehabilitation Hospital, Capital Medical University, Beijing, China.
  • 5 MOE Key Laboratory of Bioinformatics, Centre for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China.
  • 6 National Center for Protein Science, Tsinghua University, Beijing, China.
  • 7 Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. mying@zju.edu.cn.
  • 8 MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, China. yrao@tsinghua.edu.cn.
  • 9 School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China. yrao@tsinghua.edu.cn.
  • # Contributed equally.
PMID: 33664520 DOI: 10.1038/s41589-021-00742-5
Abstract

The discovery of effective therapeutic treatments for Cancer via cell differentiation instead of antiproliferation remains a great challenge. Cyclin-dependent kinase 2 (CDK2) inactivation, which overcomes the differentiation arrest of acute myeloid leukemia (AML) cells, may be a promising method for AML treatment. However, there is no available selective CDK2 Inhibitor. More importantly, the inhibition of only the enzymatic function of CDK2 would be insufficient to promote notable AML differentiation. To further validate the role and druggability of CDK2 involved in AML differentiation, a suitable chemical tool is needed. Therefore, we developed first-in-class CDK2-targeted proteolysis-targeting chimeras (PROTACs), which promoted rapid and potent CDK2 degradation in different cell lines without comparable degradation of Other targets, and induced remarkable differentiation of AML cell lines and primary patient cells. These data clearly demonstrated the practicality and importance of PROTACs as alternative tools for verifying CDK2 protein functions.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-141680
    99.33%, CDK2 Degrader