Synthesis, functional proteomics and biological evaluation of new 5-pyrazolyl ureas as potential anti-angiogenic compounds

Based on biological results of previous synthesized pyrazolyl ureas able to interfere with angiogenesis process, we planned and synthesized the new benzyl-urea derivatives 2-4; some of them showed an interesting anti-proliferative profile and particularly 4e potently inhibited HUVEC proliferation. To shed light on the mechanism of action of 4e, its interactome has been deeply inspected to identify the most prominent protein partners, mainly taking into account kinome and phosphatome, through drug affinity responsive target stability experiments, followed by targeted limited proteolysis analysis. From these studies, PP1 gamma emerged as the most reliable 4e potential target in HUVEC. Molecular docking simulations on PP1 gamma were carried out to predict 4e binding mode. To assess its potential anti-angiogenic effect, 4e was tested in vitro to verify interference on kinase and phosphate activities. Overall, our results evidenced for 4e an interesting anti-angiogenic action, probably due to its action at intracellular level on PP1 gamma signalling pathways. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

In this study, new benzyl-urea derivatives were synthesized, among which 4e showed potent inhibition of HUVEC proliferation. The potential target of 4e in HUVEC was identified as PP1 gamma through interactome analysis, suggesting an interesting anti-angiogenic action at the intracellular level.