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

Jubo Wang; Tinghan Li; Tengteng Zhao; Tizhi Wu; Chuang Liu; Hong Ding; Zhiyu Li; Jinlei Bian

doi:10.1016/j.ejmech.2019.06.024

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. Epub 2019 Jun 15.

Authors

Jubo Wang¹, Tinghan Li¹, Tengteng Zhao¹, Tizhi Wu¹, Chuang Liu², Hong Ding³, Zhiyu Li⁴, Jinlei Bian⁵

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.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Proliferation / drug effects
Cyclin-Dependent Kinase 9
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Female
Flavanones / chemical synthesis
Flavanones / chemistry
Flavanones / pharmacology*
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / pathology
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Flavanones
Protein Kinase Inhibitors
CDK9 protein, human
Cyclin-Dependent Kinase 9
wogonin