Recent updates on potential of VEGFR-2 small-molecule inhibitors as anticancer agents.

The vascular endothelial growth factor receptor (VEGFR) system is the key component for controlling angiogenesis in cancer cells. Blocking vascular endothelial growth factor receptor 2 (VEGFR2) signalling is one of the most promising approaches to hindering angiogenesis and the subsequent growth of cancer cells. The USFDA-approved small-molecule drugs targeting VEGFR-2 are developing drug resistance over the course of chemotherapy, and cardiac-related side effects are consistently being reported; hence, there is an urgent need for more safe and effective anticancer molecules. The present review focuses on the structure and physiology of VEGFR-2 and its involvement in the progression of cancer cells. The recent updates from the last five years through papers and patents on structure-activity relationships, pharmacophoric attributes, molecular docking interactions, antiangiogenic assays, cancer cell line studies, and the potencies (IC) of VEGFR-2 inhibitors are discussed herein. The common structural framework requirements, such as the Asp-Phe-Gly (DFG) motif of VEGFR-2 interacting with the HBD-HBA region in the ligand molecules, the central aryl ring occupying the linker region, and a variety of bio-isosteres, can enhance activity against VEGFR-2. At one end, the heteroaryl moiety is essential for interaction within the ATP-binding site of VEGFR-2, while the terminal hydrophobic tail occupies the allosteric binding site. Three to five bond spacers between the heteroaryl and HBD-HBA regions provided a better result towards VEGFR-2 inhibition, mirroring the behaviors of standard drugs. The in-depth analysis of recent updates on VEGFR-2 inhibitors presented in this paper will help prospective synthetic and medicinal chemists to discover new lead molecules for the treatment of various cancers.