Expanding the structural diversity of diarylureas as multi-target tyrosine kinase inhibitors

Yuanyuan Shan; Chen Wang; Lin Zhang; Jinfeng Wang; Maoyi Wang; Yalin Dong

doi:10.1016/j.bmc.2015.12.038

Expanding the structural diversity of diarylureas as multi-target tyrosine kinase inhibitors

Bioorg Med Chem. 2016 Feb 15;24(4):750-8. doi: 10.1016/j.bmc.2015.12.038. Epub 2015 Dec 23.

Authors

Yuanyuan Shan¹, Chen Wang², Lin Zhang², Jinfeng Wang², Maoyi Wang¹, Yalin Dong³

Affiliations

¹ Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, PR China.
² School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi Province, PR China.
³ Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, PR China. Electronic address: dongyalin@mail.xjtu.edu.cn.

PMID: 26753815
DOI: 10.1016/j.bmc.2015.12.038

Abstract

Recently approved multi-target inhibitors of receptor tyrosine kinases (RTKs) have significantly improved the clinical treatment of cancers. A series of N,N'-diarylureas incorporated with aromatic heterocycle have been designed, synthesized and evaluated as novel multi-target RTK inhibitors. The preliminary biological evaluation indicated that several compounds exhibited comparable potency with Sorafenib. Among them, compound 6f was identified as the most potent multikinase inhibitor of EGFR, KDR and FGFR1 with IC50 values of 14.83nM, 21.57nM, and 28.23nM, respectively. These compounds expanded the structural diversity of diarylureas as RTK inhibitors. The results demonstrated that compound 6f could be served as novel lead compound for further development of multi-target RTK inhibitors.

Keywords: Diarylurea; Inhibitor; Multi-target; Receptor tyrosine kinase; Structural diversity.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Drug Screening Assays, Antitumor
Enzyme Assays
Epithelial Cells / cytology
Epithelial Cells / drug effects
Epithelial Cells / enzymology
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / chemistry
ErbB Receptors / metabolism
Hepatocytes / cytology
Hepatocytes / drug effects
Hepatocytes / enzymology
Humans
Indoles / chemical synthesis*
Indoles / pharmacology
Molecular Docking Simulation
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / pharmacology
Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 1 / chemistry
Receptor, Fibroblast Growth Factor, Type 1 / metabolism
Structure-Activity Relationship*
Urea / analogs & derivatives
Urea / chemical synthesis*
Urea / pharmacology
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
Vascular Endothelial Growth Factor Receptor-2 / chemistry
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Antineoplastic Agents
Indoles
Protein Kinase Inhibitors
Urea
EGFR protein, human
ErbB Receptors
FGFR1 protein, human
Receptor, Fibroblast Growth Factor, Type 1
Vascular Endothelial Growth Factor Receptor-2