Development of Novel VEGFR2 Inhibitors Originating from Natural Product Analogues with Antiangiogenic Impact

A novel natural small molecule, voacangine
(Voa), has been discovered
as a potent antiangiogenic compound. Notably, Voa directly binds the
kinase domain of the vascular endothelial growth factor receptor 2
(VEGFR2) and thereby inhibits downstream signaling. Herein, we developed
synthetic small molecules based on the unique chemical structure of
Voa that directly and specifically target and modulate the kinase
activity of VEGFR2. Among these Voa structure analogues, Voa analogue
19 (V19) exhibited increased antiangiogenic potency against VEGF-induced
VEGFR2 phosphorylation without cytotoxic effects. Moreover, treatment
with V19 resulted in significant tumor cell death in a mouse xenograft
model. In conclusion, this new VEGFR2 modulator, inspired from the
rigid scaffold of a natural compound, Voa, is presented as a potent
candidate in the development of new antiangiogenic agents.