Revisiting VEGF/VEGFR-2 signalling as an anticancer target and its inhibitor discovery: where are we and where should we go?

Angiogenesis plays an important role in tumour growth and metastasis. Targeting tumour vascular endothelial cells to inhibit tumour angiogenesis and thus block tumour blood and nutrition supply is the current research focus on anti-tumour growth and metastasis. Vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR-2) signal pathway regulates the proliferation, migration, survival and angiogenesis of vascular endothelial cells, which is abnormally activated in different tumours. Studies have confirmed that inhibiting VEGF/VEGFR-2 signalling pathway can produce anti-tumour effect. Nowadays, anti-angiogenesis therapy targeting VEGF/VEGFR-2 inhibition has become the most effective clinical strategy for cancer treatment. Therefore, a variety of VEGF/VEGFR-2 inhibitors with different structures have been developed. A few selectively inhibit VEGF to block the activation of VEGFR-2 pathway, while the majority selectively inhibit VEGFR-2 as multi-target inhibitors. Based on the classification of dominant skeletons, this paper briefly analyzes the biological activity, clinical research process and structure-activity relationship of the representative small molecule inhibitors of VEGF/VEGFR-2.