ABSTRACT Vascular endothelial growth factor receptor‐2 (VEGFR‐2) is the primary mediator of tumor angiogenesis, establishing it as a premier therapeutic target in oncology. This review provides a comprehensive analysis of six‐membered heterocyclic small‐molecule inhibitors targeting the VEGFR‐2 tyrosine kinase domain. The pharmacophoric requirements for effective inhibition conform to a multicomponent model featuring: a planar heteroaromatic ring anchoring the hinge region, a central hydrophobic linker, a hydrogen‐bond donor–acceptor motif interacting with the DFG motif, and a terminal hydrophobic moiety occupying the allosteric back pocket. FDA‐approved inhibitors are classified as Type I (DFG‐in binders) or Type II (DFG‐out binders), with the latter offering enhanced selectivity. Recent advances in quinoxaline, quinazoline, quinoline, pyridine, and pyrimidine‐based inhibitors are critically evaluated, with emphasis on structure‐activity relationships, scaffold‐specific binding interactions, and comparative analysis. Key findings reveal that urea/amide motifs, 2–4 atom linkers, and para‐substituted terminal groups consistently enhance potency. Clinical limitations, including acquired resistance, off‐target toxicity, and lack of predictive biomarkers, are discussed. Future perspectives highlight emerging strategies such as PROTACs, covalent inhibitors, and AI‐assisted drug design to overcome current challenges.
Khalifa et al. (Wed,) studied this question.