Discovery of novel anti-angiogenesis agents. Part 11: Development of PROTACs based on active molecules with potency of promoting vascular normalization

  • Eur J Med Chem. 2020 Nov 1;205:112654. doi: 10.1016/j.ejmech.2020.112654.
Yuanyuan Shan  1 ,  Ru Si  2 ,  Jin Wang  2 ,  Qingqing Zhang  2 ,  Jing Li  2 ,  Yuexiang Ma  2 ,  Jie Zhang  3
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: [email protected].
PMID: 32750566 DOI: 10.1016/j.ejmech.2020.112654
Abstract

Our recent investigation is focused on the discovery of anti-angiogenesis agents. Vascular normalization induced by anti-angiogenic agent appears to be a promising strategy. We have developed novel angiogenesis inhibitors with potency of promoting vascular normalization. Herein, we reported the design, synthesis and preliminary evaluation of proteolysis-targeting chimera (PROTACs) based on the previously developed anti-angiogenesis agents. Two PROTACs exhibited potent VEGFR-2 inhibition and anti-proliferative activity against HUVECs. Moreover, they were capable of reducing protein levels of VEGFR-2 in EA.hy926 cells without significant cytotoxicity against HEK293 cells. The novel PROTACs could be used to normalize the abnormal vessels, resulting in efficient delivery of drugs.

Keywords
Active molecules; Anti-angiogenesis agents; PROTACs; Vascular normalization.
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