2. Academic Validation
  3. Discovery of novel anti-angiogenesis agents. Part 9: Multiplex inhibitors suppressing compensatory activations of RTKs

Discovery of novel anti-angiogenesis agents. Part 9: Multiplex inhibitors suppressing compensatory activations of RTKs

  • Eur J Med Chem. 2019 Feb 15:164:440-447. doi: 10.1016/j.ejmech.2018.12.067.
Yuanyuan Shan 1,  Ru Si 2,  Jin Wang 2,  Qingqing Zhang 2,  Huaxin Zhou 2,  Jie Song 2,  Jie Zhang 3,  Qinhua Chen 4
Affiliations

Affiliations

  • 1 Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
  • 2 School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China.
  • 3 School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China. Electronic address: zhj8623@mail.xjtu.edu.cn.
  • 4 Affiliated Dongfeng Hospital, Hubei University of Medicine, Shiyan, 442008, China. Electronic address: cqh77@163.com.
PMID: 30616052 DOI: 10.1016/j.ejmech.2018.12.067
Abstract

Aberrant angiogenesis is a hallmark of various diseases including cancers. VEGFR-2 inhibitors have been utilized as anti-angiogenic agents for several years. However, compensatory activation of various Receptor Tyrosine Kinases (RTK) could induce the occurrence of resistance. We previously reported a series of multi-target inhibitors of VEGFR-2, TIE-2, and EphB4 as anti-angiogenic agents. These inhibitors might be a promising strategy to overcome the resistance induced by compensatory activation. In order to expand the structural diversity of these multiple RTK inhibitors, we described herein the design, synthesis, and evaluation of a novel class of triplet VEGFR-2/TIE-2/EphB4 inhibitors. The biological evaluation indicated that five compounds (6b, 6d, 6e, 7e, and 7g) exhibited simultaneous VEGFR-2/TIE-2/EphB4 inhibitory activities with IC50 values less than 50 nM.

Keywords

1,2,3-Triazole; Anti-angiogenic agents; Compensatory activation; Multi-target; RTK inhibitors.

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