VEGFR-2 Inhibitors: Structure–Activity Relationships Across Heterocyclic Scaffolds and Cancer Biology

The growth of a tumor and the development of metastases are facilitated by tumor angiogenesis, and vascular endothelial growth factor receptor 2 (VEGFR-2) plays an essential role in the process of angiogenesis. Receptor tyrosine kinases involved in the process of angiogenesis have become the primary focus of anticancer drug design. This review focuses on the role of VEGFR-2 in breast, lung, and colorectal cancers; solid and hematologic tumors; and leukemia. In addition, it provides a summary of recent findings regarding the medicinal chemistry of VEGFR-2 inhibitors. This review is organized by ten heterocyclic scaffolds, including imidazole, quinazoline, pyridine, pyrimidine, indole, purine, indazole, quinoline, quinoxaline, and triazole, and outlines SAR and pharmacophore contributions. The ten most active compounds were evaluated using docking. The results of this evaluation showed that most of the identified compounds were more active than sorafenib in displacing the DFG motif and the hydrophobic binding pocket and interacting with the hydrophobic binding pocket rather than the typical hinge-region bond. The last section of this review outlines some possible approaches to develop new, more selective and clinically relevant VEGFR-2 inhibitors. These approaches include the use of mutant-specific inhibitors and structure-based design in combination with molecular hybridization.