Design, synthesis and structure-activity relationship of diaryl-ureas with novel isoxazol[3,4-b]pyridine-3-amino-structure as multi-target inhibitors against receptor tyrosine kinase

Zhi-Hao Shi; Feng-Tao Liu; Hao-Zhong Tian; Yan-Min Zhang; Nian-Guang Li; Tao Lu

doi:10.1016/j.bmc.2018.08.013

Design, synthesis and structure-activity relationship of diaryl-ureas with novel isoxazol[3,4-b]pyridine-3-amino-structure as multi-target inhibitors against receptor tyrosine kinase

Bioorg Med Chem. 2018 Sep 1;26(16):4735-4744. doi: 10.1016/j.bmc.2018.08.013. Epub 2018 Aug 11.

Authors

Zhi-Hao Shi¹, Feng-Tao Liu¹, Hao-Zhong Tian¹, Yan-Min Zhang¹, Nian-Guang Li², Tao Lu³

Affiliations

¹ Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China.
² National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, Jiangsu 210023, China. Electronic address: linianguang@njucm.edu.cn.
³ Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China. Electronic address: lutao@cpu.edu.cn.

PMID: 30121211
DOI: 10.1016/j.bmc.2018.08.013

Abstract

Inspired by that the multi-target inhibitors against receptor tyrosine kinases (RTKs) have significantly improved the effect of clinical treatment for cancer, and based on the chemical structure of Linifanib (ABT-869, Abbott), two series of diaryl-ureas with novel isoxazol[3,4-b]pyridine-3-amino-structure were designed and synthesized as multi-target inhibitors against RTKs. The preliminary biological evaluation showed that several compounds exhibited comparable potency with Linifanib. Compound S21 was identified as the most potent inhibitor against Fms-like tyrosine kinase 3 (FLT-3), kinase insert domain containing receptor (KDR) and platelet-derived growth factor receptor β (PDGFR-β) with its IC₅₀ values were 4 nM, 3 nM and 8 nM respectively, it also showed potent inhibitory activities against several cancer cells.

Keywords: Antiangiogenesis; FLT3; KDR; Multi-target inhibitors; PDGFR-β; Receptor tyrosine kinase.

Publication types

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

MeSH terms

Binding Sites
Cell Line
Cell Proliferation / drug effects
Drug Design*
Humans
Molecular Docking Simulation
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / pharmacology
Protein Structure, Tertiary
Pyridines / chemistry*
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
Receptor Protein-Tyrosine Kinases / metabolism*
Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors
Structure-Activity Relationship
Urea / chemistry*
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

Protein Kinase Inhibitors
Pyridines
Urea
Receptor Protein-Tyrosine Kinases
Receptor, Platelet-Derived Growth Factor beta
Vascular Endothelial Growth Factor Receptor-2
fms-Like Tyrosine Kinase 3