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

Junyu Xu; Hongmei Li; Xinren Wang; Jianhang Huang; Shuwen Li; Chenhe Liu; Ruinan Dong; Gaoyuan Zhu; Chunqi Duan; Fei Jiang; Yanmin Zhang; Yuqin Zhu; Tianyi Zhang; Yadong Chen; Weifang Tang; Tao Lu

doi:10.1016/j.ejmech.2020.112424

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. Epub 2020 May 15.

Authors

Junyu Xu¹, Hongmei Li², Xinren Wang², Jianhang Huang², Shuwen Li², Chenhe Liu², Ruinan Dong², Gaoyuan Zhu², Chunqi Duan², Fei Jiang², Yanmin Zhang³, Yuqin Zhu², Tianyi Zhang², Yadong Chen⁴, Weifang Tang⁵, Tao Lu⁶

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: ydchen@cpu.edu.cn.
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: twf@cpu.edu.cn.
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: lutao@cpu.edu.cn.

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.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Coumarins / chemical synthesis
Coumarins / chemistry
Coumarins / pharmacology*
Cyclin-Dependent Kinase 9 / antagonists & inhibitors*
Cyclin-Dependent Kinase 9 / metabolism
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Female
Humans
Male
Mice
Mice, Inbred BALB C
Mice, Inbred ICR
Mice, Nude
Models, Molecular
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / metabolism
Neoplasms, Experimental / pathology
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

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