Vascular endothelial growth factor receptor 1, 2, and 3 (VEGFR1/2/3)

Vascular endothelial growth factor receptors (VEGFR1, VEGFR2, and VEGFR3) are a family of receptor tyrosine kinases that serve as critical regulators of blood and lymphatic vessel formation [8, 14]. VEGFR1 and VEGFR2 are primarily expressed on vascular endothelial cells and are the main mediators of angiogenesis, while VEGFR3 is predominantly found on lymphatic endothelial cells and governs lymphangiogenesis [6, 18]. In many cancers, these receptors are overexpressed or hyperactivated, driving the development of a robust vascular network that supports tumor growth and facilitates metastatic spread [9, 11]. Anlotinib is a potent, orally administered small-molecule TKI designed to inhibit all three VEGFR subtypes with high affinity, particularly VEGFR2 and VEGFR3 [2, 5]. By blocking these targets, anlotinib effectively disrupts the pro-angiogenic signaling within the tumor microenvironment, leading to reduced microvessel density and tumor starvation [4, 12]. Beyond the VEGFR family, anlotinib also targets other kinases such as PDGFR, FGFR, and c-Kit, providing a broad-spectrum anti-tumor effect that has led to its clinical approval for treating advanced non-small cell lung cancer, small cell lung cancer, and various soft tissue sarcomas [1, 17, 19].

Other names

VEGF receptor familyFms-like tyrosine kinase 1 (FLT1)Kinase insert domain receptor (KDR)Fetal liver kinase 1 (FLK1)Fms-like tyrosine kinase 4 (FLT4)Vascular endothelial growth factor receptor

Anlotinib and other multi-targeted tyrosine kinase inhibitors (TKIs) bind to the intracellular ATP-binding pocket of the VEGFR1, VEGFR2, and VEGFR3 kinase domains [2, 5]. This binding prevents the autophosphorylation of the receptors upon ligand binding (such as VEGF-A, -C, or -D), thereby blocking downstream signaling cascades including the MAPK/ERK and PI3K/Akt pathways [4, 6]. This inhibition leads to the suppression of endothelial cell proliferation, migration, and survival, effectively halting tumor-induced angiogenesis and lymphangiogenesis [1, 16].