Discovery of thiazolidin-4-one urea analogues as novel multikinase inhibitors that potently inhibit FLT3 and VEGFR2

Baohui Qi; Xingwei Xu; Ying Yang; Yuting Zhou; Tao Chen; Guowei Gong; Xupeng Yue; Xin Xu; Liping Hu; Huan He

doi:10.1016/j.bmc.2019.03.049

Discovery of thiazolidin-4-one urea analogues as novel multikinase inhibitors that potently inhibit FLT3 and VEGFR2

Bioorg Med Chem. 2019 May 15;27(10):2127-2139. doi: 10.1016/j.bmc.2019.03.049. Epub 2019 Mar 25.

Authors

Baohui Qi¹, Xingwei Xu², Ying Yang², Yuting Zhou², Tao Chen², Guowei Gong², Xupeng Yue², Xin Xu², Liping Hu², Huan He³

Affiliations

¹ Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai 519041, Guangdong Province, China. Electronic address: bhqi@zmu.gd.cn.
² Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai 519041, Guangdong Province, China.
³ Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai 519041, Guangdong Province, China. Electronic address: hehuan_1029@163.com.

PMID: 30940564
DOI: 10.1016/j.bmc.2019.03.049

Abstract

A series of novel thiazolidine-4-one urea analogues were designed, synthesized and biologically evaluated. The structure-activity relationship (SAR) at several positions of the scaffolds was investigated and its binding mode was analyzed by molecular modeling studies. Compound 17b proved to be the most potent one, and IC₅₀ values against A549 and HT-29 cancer cell lines were 0.65 μM and 0.11 μM, respectively. The results of kinase profile demonstrated that compound 17b is a multikinase inhibitor that potently inhibits FLT3 (IC₅₀ = 8.6 nM) and VEGFR2 (IC₅₀ = 18.7 nM). The results of real-time live-cell imaging indicated that compound 17b showed excellent cytotoxicity and anti-proliferative activity against HT-29 cancer cells in a time- and dose-dependent manner, which was significantly potent than that of Cabozantinib. In addition, in vitro antitumor activity was associated with inducing cancer cell apoptosis and suppression of cancer cell migration.

Keywords: Anti-tumor; FLT3; Kinase inhibitor; Structure-activity relationship; Thiazolidin-4-one; VEGFR2.

Publication types

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

MeSH terms

Anilides / pharmacology
Apoptosis / drug effects
Binding Sites
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Design
Humans
Molecular Docking Simulation
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology
Protein Structure, Tertiary
Pyridines / pharmacology
Structure-Activity Relationship
Thiazolidinediones / chemistry*
Urea / analogs & derivatives*
Urea / metabolism
Urea / pharmacology
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / metabolism
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
fms-Like Tyrosine Kinase 3 / metabolism

Substances

Anilides
Protein Kinase Inhibitors
Pyridines
Thiazolidinediones
cabozantinib
Urea
Vascular Endothelial Growth Factor Receptor-2
fms-Like Tyrosine Kinase 3