Design, synthesis and biological evaluation of thienopyridinones as Chk1 inhibitors

Pinrao Song; Peng Peng; Mengmeng Han; Xianchao Cao; Xiaodong Ma; Tao Liu; Yubo Zhou; Yongzhou Hu

doi:10.1016/j.bmc.2014.06.044

Design, synthesis and biological evaluation of thienopyridinones as Chk1 inhibitors

Bioorg Med Chem. 2014 Sep 1;22(17):4882-92. doi: 10.1016/j.bmc.2014.06.044. Epub 2014 Jun 28.

Authors

Pinrao Song¹, Peng Peng¹, Mengmeng Han², Xianchao Cao², Xiaodong Ma¹, Tao Liu³, Yubo Zhou⁴, Yongzhou Hu⁵

Affiliations

¹ ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
² National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: lt601@zju.edu.cn.
⁴ National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: ybzhou@mail.shcnc.ac.cn.
⁵ ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: huyz@zju.edu.cn.

PMID: 25042558
DOI: 10.1016/j.bmc.2014.06.044

Abstract

A series of thienopyridinone derivatives was designed and synthesized as inhibitors of checkpoint kinase 1 (Chk1). Most of them exhibited moderate to good Chk1 inhibitory activities. Among them, compounds 8q, 8t, and 8w with excellent Chk1 inhibitory activities (IC50 values of 4.05, 6.23, and 2.33nM, respectively) displayed strong synergistic effects with melphalan, a DNA-damaging agent in the cell-based assay. Further kinase profiling indicated that compound 8t was highly selective against CDK2/cyclinA, Aurora A, and PKC.

Keywords: Antitumor; Cell synergy; Chk1 inhibitor; Thienopyridinones.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Cell Proliferation / drug effects
Checkpoint Kinase 1
Dose-Response Relationship, Drug
Drug Design*
Humans
Molecular Docking Simulation
Molecular Structure
Multiple Myeloma / drug therapy*
Multiple Myeloma / pathology
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Kinases / metabolism*
Pyridones / chemical synthesis
Pyridones / chemistry
Pyridones / pharmacology*
Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
Pyridones
Protein Kinases
CHEK1 protein, human
Checkpoint Kinase 1