2. Academic Validation
  3. Discovery of novel imidazo[1,2-b]pyridazine derivatives as potent covalent inhibitors of CDK12/13

Discovery of novel imidazo[1,2-b]pyridazine derivatives as potent covalent inhibitors of CDK12/13

  • Eur J Med Chem. 2025 Apr 15:288:117378. doi: 10.1016/j.ejmech.2025.117378.
Meng Xia 1,  Ziteng Li 2,  Hanrui Jiang 3,  Yuanqing Li 4,  Linghao Hu 5,  Yongchang He 5,  Siqi Huang 5,  Lei Tang 6,  Cheng Luo 7,  Shuangxi Gu 8,  Hong Ding 9,  Mingliang Wang 10
Affiliations

Affiliations

  • 1 State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmacy, Guizhou Medical University, Guiyang, 550004, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
  • 3 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China; Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering & Pharmacy, Wuhan Institute of Technology, Wuhan, 430205, China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China.
  • 5 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China.
  • 6 State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmacy, Guizhou Medical University, Guiyang, 550004, China.
  • 7 State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmacy, Guizhou Medical University, Guiyang, 550004, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China; The School of Pharmacy, Fujian Medical University, Fuzhou, 350122, China.
  • 8 Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering & Pharmacy, Wuhan Institute of Technology, Wuhan, 430205, China. Electronic address: shuangxigu@163.com.
  • 9 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China. Electronic address: hding@simm.ac.cn.
  • 10 State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmacy, Guizhou Medical University, Guiyang, 550004, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China. Electronic address: wangmingliang@simm.ac.cn.
PMID: 39955845 DOI: 10.1016/j.ejmech.2025.117378
Abstract

Triple-negative breast Cancer (TNBC) is widely recognized as the most aggressive subtype of breast Cancer, and treatment options for patients with TNBC remain highly limited. Recently, cyclin-dependent kinases 12/13 (CDK12/13) have been identified as promising therapeutic targets for TNBC. In our study, we report the design and synthesis of novel imidazo[1,2-b]pyrazine-based covalent inhibitors of CDK12/13, which exhibit potent inhibitory activity against TNBC cells. Among these compounds, compound 24 emerged as the most potent inhibitor, with CDK12 IC50 of 15.5 nM and CDK13 IC50 of 12.2 nM. Compound 24 forms a covalent bond with Cys1039 of CDK12 and effectively suppresses the proliferation of TNBC cell lines MDA-MB-231 and MDA-MB-468, with EC50 values of 5.0 nM and 6.0 nM, respectively. Compound 24 demonstrated superior efficacy to the currently known CDK12/13 covalent inhibitor, THZ531. These findings suggest compound 24 may be a promising lead for developing CDK12/13-targeted therapies for treating TNBC.

Keywords

CDK12/13 covalent inhibitors; Cys1039; THZ531; Triple-negative breast cancer.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-173042
    CDK12/13 抑制剂
    CDK
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