2. Academic Validation
  3. Discovery of Wogonin-based PROTACs against CDK9 and capable of achieving antitumor activity

Discovery of Wogonin-based PROTACs against CDK9 and capable of achieving antitumor activity

  • Bioorg Chem. 2018 Dec;81:373-381. doi: 10.1016/j.bioorg.2018.08.028.
Jinlei Bian 1,  Jie Ren 2,  Yongren Li 3,  Jubo Wang 2,  Xi Xu 2,  Yifan Feng 2,  Hui Tang 2,  Yajing Wang 4,  Zhiyu Li 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: bianjl@cpu.edu.cn.
  • 2 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
  • 3 College of Life Science and Technology, P. R. China Pharmaceutical University, Nanjing 210009, PR China.
  • 4 Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
  • 5 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: Zhiyuli@cpu.edu.cn.
PMID: 30196207 DOI: 10.1016/j.bioorg.2018.08.028
Abstract

Wogonin is a natural product isolated from the Scutellaria baicalensis and has been proved to be a potent and selective inhibitor of CDK9. Using this scaffold, we designed and synthesized a series of proteolysis targeting chimeras (PROTACs) targeting CDK9 by recruiting ubiquitin E3 ligase Cereblon (CRBN). For constructing diverse Wogonin-based PROTACs, a "click chemistry" approach was employed for the synthesis of CDK9-targeting PROTACs. The results of western blotting assays showed that compounds containing triazole group in the linker could selectively downregulate the intracellular CDK9 level. Among these compounds, 11c could selectively degrade CDK9 in a concentration-dependent manner. In addition, the application of the Proteasome Inhibitor MG132 and CRBN siRNA silencing confirmed that 11c could promote the proteasome-dependent and CRBN-dependent degradation. Consistent with the degradation of the CDK9 protein, 11c selectively inhibits proliferation of CDK9-overexpressed Cancer cells. Thus, our Wogonin-based PROTAC would be an efficient probe that induces the degradation of CDK9.

Keywords

Antitumor; CDK9; Click Chemistry; PROTAC; Wogonin.

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