Key result
Compound 7a, a novel VEGFR-2 inhibitor, significantly increased caspase-3 levels by 7.80-fold, induced apoptosis, reduced TNF-α by 87%, and inhibited smooth muscle proliferation in vitro.
Why the study?
Abnormal VSMC proliferation contributes to atherosclerosis restenosis and hypertension, and VEGFR-2 blockage suppresses angiogenesis, motivating the discovery of novel VEGFR-2 TK inhibitors.
Effect estimate: 7.80-fold increase in caspase-3
Compound 7a is a novel VEGFR-2 inhibitor that demonstrates potent anti-proliferative, pro-apoptotic, and immunomodulatory effects in cancer and vascular smooth muscle cell lines.
Abnormal vascular smooth muscle cell (VSMC) proliferation has an important role in the pathogenesis of both atherosclerosis restenosis and hypertension. Vascular endothelial growth factor (VEGF) has been shown to stimulate VSMC proliferation. In addition, angiogenesis is one of the hallmarks of cancerous growth. VEGF is the key modulator for the initial stages of angiogenesis that acts through the endothelial‐specific receptor tyrosine kinases (VEGFRs). VEGFR‐2 blockage is a good approach for suppression of angiogenesis. In order to discover novel VEGFR‐2 TK inhibitors, we have designed and synthesized three new series of pyridine‐containing compounds. The new compounds were all screened against a panel of three cell lines (HepG‐2, HCT‐116, and MCF‐7). Promising results encouraged us to additionally evaluate the most active members for their in vitro VEGFR‐2 inhibitory effect. Compound 7a, which is the most potent candidate, revealed a significant increase in caspase‐3 level by 7.80‐fold when compared to the control. In addition, Bax and Bcl‐2 concentration levels showed an increase in the proapoptotic protein Bax (261.4 Pg/ml) and a decrease of the antiapoptotic protein Bcl‐2 (1.25 Pg/ml) compared to the untreated cells. Furthermore, compound 7a arrested the cell cycle in the G2/M phase with induction of apoptosis. The immunomodulatory effect of compound 7a, the most active member, showed a reduction in TNF‐ α by 87%. Also, compound 7a caused a potent inhibitory effect on smooth muscle proliferation. Docking studies were also performed to get better insights into the possible binding mode of the target compounds with VEGFR‐2 active sites.
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Ran et al. (2021) studied Cancer and vascular smooth muscle cell proliferation. Compound 7a (novel VEGFR-2 inhibitor) vs. untreated control was evaluated on caspase-3 level, apoptosis markers, and TNF-α reduction (7.80-fold increase in caspase-3). Compound 7a, a novel VEGFR-2 inhibitor, significantly increased caspase-3 levels by 7.80-fold, induced apoptosis, reduced TNF-α by 87%, and inhibited smooth muscle proliferation in vitro.
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