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

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.