2. Academic Validation
  3. Discovery of thiazolidin-4-one urea analogues as novel multikinase inhibitors that potently inhibit FLT3 and VEGFR2

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.
Baohui Qi 1,  Xingwei Xu 2,  Ying Yang 2,  Yuting Zhou 2,  Tao Chen 2,  Guowei Gong 2,  Xupeng Yue 2,  Xin Xu 2,  Liping Hu 2,  Huan He 3
Affiliations

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/KDR/Flk-1 (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.

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