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.

Chuansheng Li ¹, Yuanyuan Shan ², Ying Sun ¹, Ru Si ¹, Liyuan Liang ¹, Xiaoyan Pan ¹, Binghe Wang ³, Jie Zhang ⁴

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.

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