Tyrosine-protein kinase receptor UFO (AXL), Macrophage-stimulating protein receptor (RON), and Vascular endothelial growth factor receptor 2 (VEGFR2) (AXL/RON/VEGFR2)

The target profile comprising Tyrosine-protein kinase receptor UFO (AXL), Macrophage-stimulating protein receptor (RON), and Vascular endothelial growth factor receptor 2 (VEGFR2) represents a multi-kinase inhibitory signature often targeted in advanced oncology (UniProt P30530, Q04912, P35968). AXL and RON are receptor tyrosine kinases that play critical roles in promoting epithelial-to-mesenchymal transition (EMT), tumor cell invasion, and resistance to targeted therapies like EGFR inhibitors. VEGFR2 is the primary receptor mediating angiogenesis, which is essential for the nutrient supply and metastatic spread of solid tumors. By simultaneously inhibiting these pathways, therapeutic agents aim to disrupt both the internal survival signaling of the tumor and the external support provided by the tumor microenvironment. This multi-targeted approach is particularly effective in overcoming bypass signaling mechanisms that lead to drug resistance in cancers such as non-small cell lung cancer and renal cell carcinoma. Drugs like BMS-777607 and cabozantinib are designed to hit this specific profile to achieve broader efficacy than single-target inhibitors (PMID: 19808981). The inclusion of other weak off-target kinases in this profile typically refers to the inherent cross-reactivity of small-molecule inhibitors within the kinome, which may contribute to both secondary efficacy and systemic toxicity. However, the broad inhibition of these essential signaling pathways can lead to significant clinical safety concerns, including hypertension and gastrointestinal toxicity.

Other names

AXLRONVEGFR2MST1RKDRUFOAXL/RON/VEGFR2 multi-kinase profileTAM/MET/VEGFR family kinases

Simultaneous competitive inhibition of the ATP-binding sites of AXL, RON, and VEGFR2 receptor tyrosine kinases, leading to suppressed tumor growth, invasion, and angiogenesis.