2. Academic Validation
  3. Design of wogonin-inspired selective cyclin-dependent kinase 9 (CDK9) inhibitors with potent in vitro and in vivo antitumor activity

Design of wogonin-inspired selective cyclin-dependent kinase 9 (CDK9) inhibitors with potent in vitro and in vivo antitumor activity

  • Eur J Med Chem. 2019 Sep 15:178:782-801. doi: 10.1016/j.ejmech.2019.06.024.
Jubo Wang 1,  Tinghan Li 1,  Tengteng Zhao 1,  Tizhi Wu 1,  Chuang Liu 2,  Hong Ding 3,  Zhiyu Li 4,  Jinlei Bian 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China.
  • 2 Department of Biochemistry, China Pharmaceutical University, Nanjing 211198, China.
  • 3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.
  • 4 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: zhiyuli@cpu.edu.cn.
  • 5 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China. Electronic address: bianjl@cpu.edu.cn.
PMID: 31238183 DOI: 10.1016/j.ejmech.2019.06.024
Abstract

Wogonin, a natural product isolated from the plant Scutellaria baicalensis, has been shown to be a potent and selective inhibitor of CDK9. With the purpose of investigating the activity and selectivity of this chemical scaffold, several series of wogonin derivatives were prepared and screened for CDK9 inhibition and cellular antiproliferative activity. Among these compounds, the drug-like compound 51 showed potent activity against CDK9 (IC50 = 19.9 nM) and MV4-11 cell growth (IC50 = 20 nM). In addition, compound 51 showed much improved physicochemical properties, such as water solubility, compared with the parent compound wogonin. The follow-up studies showed that the compound 51 is selective toward CDK9-overexpressing Cancer cells over normal cells. Preliminary mechanism studies on the Anticancer effect indicated that 51 inhibited the proliferation of MV4-11 cells via caspase-dependent Apoptosis. In addition, highlighted compound 51 showed significant antitumor activity in mouse acute myeloid leukemia (AML) models without producing apparent toxic effects in vivo, which gave us a new tool for further investigation of CDK9-targeted inhibitor as a potential antitumor drug especially for AML.

Keywords

AML; Antitumor; CDK9; Flavonoid; Wogonin.

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