Design, synthesis, and biological evaluation of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives as potent CDK2 inhibitors

Tingting Lin; Jiacheng Li; Liping Liu; Yuanqing Li; Hualiang Jiang; Kaixian Chen; Pan Xu; Cheng Luo; Bing Zhou

doi:10.1016/j.ejmech.2021.113281

Design, synthesis, and biological evaluation of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives as potent CDK2 inhibitors

Eur J Med Chem. 2021 Apr 5:215:113281. doi: 10.1016/j.ejmech.2021.113281. Epub 2021 Feb 11.

Authors

Tingting Lin¹, Jiacheng Li², Liping Liu², Yuanqing Li², Hualiang Jiang³, Kaixian Chen³, Pan Xu⁴, Cheng Luo⁵, Bing Zhou⁶

Affiliations

¹ Shanghai Institute for Advanced Immunochemical Studies, and School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China; The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China.
² The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China.
³ Shanghai Institute for Advanced Immunochemical Studies, and School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China; The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China.
⁴ The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China. Electronic address: xupan_322@simm.ac.cn.
⁵ Shanghai Institute for Advanced Immunochemical Studies, and School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China; The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China. Electronic address: cluo@simm.ac.cn.
⁶ Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China. Electronic address: zhoubing@simm.ac.cn.

PMID: 33611192
DOI: 10.1016/j.ejmech.2021.113281

Abstract

Cyclin-dependent kinases play significant roles in cell cycle progression and are promising targets for cancer therapy. However, most potent CDK inhibitors lack the balance between efficacy and safety because of poor selectivity. Given the roles of CDK2 in tumorigenesis, selective CDK2 inhibition may provide therapeutic benefits against certain cancer. In this study, a series of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives were designed, synthesized, and evaluated. The most selective compound DC-K2in212 in this series exhibited high potency towards CDK2 and had effective anti-proliferative activity against A2058 melanoma cell line and MV4-11 leukemia cell line while exhibiting low toxic effect on human normal cell lines MRC5 and LX2. The molecular modeling illustrated that compound DC-K2in212 had the similar binding mode with CDK2 as C-73, the most selective CDK2 inhibitor reported so far, which might account for selectivity against CDK2 over CDK1. Further biological studies revealed that compound DC-K2in212 suppressed CDK2-associated downstream signaling pathway, blocked cell cycle progression, and induced cellular apoptosis. Therefore, compound DC-K2in212 could serve as a potential CDK2 inhibitor for further development.

Keywords: Anti-proliferative potency; CDK2 inhibitor; Selectivity.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Benzamides / chemical synthesis
Benzamides / metabolism
Benzamides / pharmacology*
Cell Cycle Checkpoints / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cyclin-Dependent Kinase 2 / antagonists & inhibitors*
Cyclin-Dependent Kinase 2 / metabolism
Drug Design
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation
Molecular Structure
Protein Binding
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology*
Pyrazoles / chemical synthesis
Pyrazoles / metabolism
Pyrazoles / pharmacology*
Signal Transduction / drug effects
Structure-Activity Relationship

Substances

Antineoplastic Agents
Benzamides
Protein Kinase Inhibitors
Pyrazoles
CDK2 protein, human
Cyclin-Dependent Kinase 2