2. Academic Validation
  3. Discovery of coumarin derivatives as potent and selective cyclin-dependent kinase 9 (CDK9) inhibitors with high antitumour activity

Discovery of coumarin derivatives as potent and selective cyclin-dependent kinase 9 (CDK9) inhibitors with high antitumour activity

  • Eur J Med Chem. 2020 Aug 15;200:112424. doi: 10.1016/j.ejmech.2020.112424.
Junyu Xu 1,  Hongmei Li 2,  Xinren Wang 2,  Jianhang Huang 2,  Shuwen Li 2,  Chenhe Liu 2,  Ruinan Dong 2,  Gaoyuan Zhu 2,  Chunqi Duan 2,  Fei Jiang 2,  Yanmin Zhang 3,  Yuqin Zhu 2,  Tianyi Zhang 2,  Yadong Chen 4,  Weifang Tang 5,  Tao Lu 6
Affiliations

Affiliations

  • 1 School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China; Hainan province Key Laboratory for Research and Development of Tropical Herbs, Hainan Medical University, Haikou, 571199, China.
  • 2 School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China.
  • 3 School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China; Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China.
  • 4 School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China; Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China. Electronic address: [email protected].
  • 5 School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China. Electronic address: [email protected].
  • 6 School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China; Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China. Electronic address: [email protected].
PMID: 32447197 DOI: 10.1016/j.ejmech.2020.112424
Abstract

Specific inhibition of CDK9 is considered a promising strategy for developing effective Anticancer therapeutics. However, most of the reported CDK9 inhibitors are still at an early stage of development and lack selectivity against other CDKs. Herein, we discovered coumarin derivative 30i as a potent CDK9 Inhibitor with high selectivity (8300-fold over CDK7). Binding mode analysis illustrated that the substituent coumarin moiety is a critical group for CDK9 selectivity by occupying a flexible hinge/αD region, which is sterically hindered in other CDKs. Compound 30i showed excellent cellular antiproliferative activity, moderate pharmacokinetic property and low hERG inhibition. Moreover, 30i significantly induced tumour growth inhibition in a dose-dependent manner without causing an obvious loss of body weight in an MV4-11 xenograft mice model. Altogether, these results suggest that 30i may serve as a potential acute myeloid leukaemia (AML) therapeutics by selectively targeting CDK9.

Keywords

Antitumour activity; CDK9 inhibitor; Coumarin derivatives; Selectivity; Structure-activity relationship.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-150562
    CDK9 Inhibitor
    CDK