Chemical scaffolds, structure-activity relationships, and therapeutic potential of EphA2 small-molecule inhibitors.
EphA2 (ephrin type-A receptor 2) is a representative member of the Eph receptor tyrosine kinase family and is frequently overexpressed in a broad spectrum of malignant tumors. It participates in regulating tumor cell proliferation, migration, invasion, and angiogenesis through ligand-dependent and ligand-independent signaling pathways, thus emerging as a promising target for anticancer drug discovery. In recent years, extensive research has been carried out toward the discovery and optimization of small-molecule EphA2 inhibitors, covering a variety of chemical scaffolds with distinct mechanisms of action. This review provides a comprehensive overview of the research progress of EphA2-targeted small-molecule inhibitors reported to date. We systematically summarize their representative chemical scaffolds, structure-activity relationships, binding modes, and pharmacological profiles, and highlight the current challenges in selectivity, pharmacokinetic properties, and clinical translation. This review is expected to offer valuable guidance for the rational design and optimization of next-generation EphA2-targeted therapeutics.