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Abstract
Lenvatinib is an oral multikinase inhibitor that selectively inhibits vascular endothelial
growth factor (VEGF) receptors 1 to 3 and other proangiogenic and oncogenic pathway-related
receptor tyrosine kinases. To elucidate the origin of the potency of lenvatinib in
VEGF receptor 2 (VEGFR2) inhibition, we conducted a kinetic interaction analysis of
lenvatinib with VEGFR2 and X-ray analysis of the crystal structure of VEGFR2-lenvatinib
complexes. Kinetic analysis revealed that lenvatinib had a rapid association rate
constant and a relatively slow dissociation rate constant in complex with VEGFR2.
Co-crystal structure analysis demonstrated that lenvatinib binds at its ATP mimetic
quinoline moiety to the ATP binding site and to the neighboring region via a cyclopropane
ring, adopting an Asp-Phe-Gly (DFG)-"in" conformation. These results suggest that
lenvatinib is very distinct in its binding mode of interaction compared to the several
approved VEGFR2 kinase inhibitors.