Distinct Binding Mode of Multikinase Inhibitor Lenvatinib Revealed by Biochemical Characterization

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.

E7090, a Novel Selective Inhibitor of Fibroblast Growth Factor Receptors, Displays Potent Antitumor Activity and Prolongs Survival in Preclinical Models

“…E7090 succinate had interaction kinetics with FGFR1 kinases intermediate between those of the two representative inhibitors, and the residence time of E7090 succinate was 19 minutes. These data suggest that the interaction of E7090 with FGFR1 possesses unique kinetics among selective FGFR inhibitors, similar to that of type V inhibitors (23).…”

“…To gain insight into the mode of interaction between E7090 succinate and FGFR1, we analyzed the kinetics of the interaction by using the Proteros reporter displacement assay (23). We also determined the kinetic parameters for the interactions of FGFR1 with AZD4547 and ponatinib, which, from their cocrystal structures, are representative type I and type II FGFR1 inhibitors, respectively (24).…”

Lenvatinib induces early tumor shrinkage in patients with advanced thyroid carcinoma

“…It is an oral multikinase inhibitor of vascular endothelial growth factor (VEGF) receptor (VEGFR)1-3, fibroblast growth factor receptor (FGFR)1-4, platelet-derived growth factor receptor alpha (PDGFR-α), ret proto-oncogene (RET), and KIT proto-oncogene [3][4][5]. In the phase 3 trial, lenvatinib prolonged progression-free survival (PFS; hazard ratio for progression or death, 0.21; 99 %CI, 0.14-0.31, p<0.001) by 14.7 months (lenvatinib median PFS, 8.3 months) compared with placebo (median PFS, 3.6 months) [6].…”

Crystal structure, Hirshfeld analysis and molecular docking with the vascular endothelial growth factor receptor-2 of (3Z)-5-fluoro-3-(hydroxyimino)indolin-2-one

“…The protein kinases regulate several critical cellular processes (Wang & Cole, 2014) and the vascular endothelial growth factor receptor-2 kinase inhibition is becoming an attractive subject for anticancer drug research (Gao et al, 2015). The crystal structure of the vascular endothelial growth factor receptor-2 (VEGFR-2), PDB ID: 3WZD, was downloaded from Protein Data Bank (Okamoto et al, 2015). Before the calculations, a stereochemical evaluation of the protein structure was carried out using the Ramachandran analysis (Lovell et al, 2003) and the number of residues in favoured regions for intermolecular interactions was over 98% [see the 'Number of residues in favoured region (VEGFR-2)' in the Supporting information].…”

“…Before the calculations, a stereochemical evaluation of the protein structure was carried out using the Ramachandran analysis (Lovell et al, 2003) and the number of residues in favoured regions for intermolecular interactions was over 98% [see the 'Number of residues in favoured region (VEGFR-2)' in the Supporting information]. The docking simulation was performed with the GOLD 5.5 software (Chen, 2015) and a grid of 25 Å was centered on the binding site of Levatinib in the VEGFR-2 kinase (Okamoto et al, 2015). A redocking of the Levatinib compound, an oral multikinase inhibitor that selectively inhibits the vascular endothelial growth factor-2, was used as validation method for the molecular docking protocol (see the 'Re-docking of the (Fig.…”