Discovery of novel anti-angiogenesis agents. Part 7: Multitarget inhibitors of VEGFR-2, TIE-2 and EphB4

Chuansheng Li; Yuanyuan Shan; Ying Sun; Ru Si; Liyuan Liang; Xiaoyan Pan; Binghe Wang; Jie Zhang

doi:10.1016/j.ejmech.2017.10.030

Discovery of novel anti-angiogenesis agents. Part 7: Multitarget inhibitors of VEGFR-2, TIE-2 and EphB4

Eur J Med Chem. 2017 Dec 1:141:506-518. doi: 10.1016/j.ejmech.2017.10.030. Epub 2017 Oct 12.

Authors

Chuansheng Li¹, Yuanyuan Shan², Ying Sun¹, Ru Si¹, Liyuan Liang¹, Xiaoyan Pan¹, Binghe Wang³, Jie Zhang⁴

Affiliations

¹ School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an 710061, China.
² Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
³ Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, United States.
⁴ School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an 710061, China. Electronic address: zhj8623@xjtu.edu.cn.

PMID: 29102175
DOI: 10.1016/j.ejmech.2017.10.030

Abstract

Herein, we embarked on a structural optimization campaign aiming at the discovery of second generation anti-angiogenesis agents with our previously reported BPS-7 as lead compound. A library of 27 compounds has been afforded based on the highly conserved ATP-binding pocket of VEGFR-2, Tie-2, and EphB4. Several title compounds exhibited simultaneous inhibitory effects against three angiogenic RTKs. These compounds with a 'triplet' inhibition profile have been identified as novel anti-angiogenic and anticancer agents. The representative VDAU11 displayed prominent anti-angiogenic and anticancer potency and could be considered as a candidate for further optimization. These results indicate that N-(pyridin-2-yl)acrylamide could serve as a novel hinge-binding group of triple inhibitors.

Keywords: Angiogenic RTKs; Anti-angiogenesis agents; Hinge-binding group; N-(pyridin-2-yl)acrylamide; Triple inhibitors.

MeSH terms

Angiogenesis Inhibitors / chemical synthesis
Angiogenesis Inhibitors / chemistry
Angiogenesis Inhibitors / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Neovascularization, Pathologic / drug therapy*
Neovascularization, Pathologic / metabolism
Neovascularization, Pathologic / pathology
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Receptor, EphB4 / antagonists & inhibitors*
Receptor, EphB4 / metabolism
Receptor, TIE-2 / antagonists & inhibitors*
Receptor, TIE-2 / metabolism
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Angiogenesis Inhibitors
Antineoplastic Agents
Protein Kinase Inhibitors
KDR protein, human
Receptor, EphB4
Receptor, TIE-2
Vascular Endothelial Growth Factor Receptor-2