title: 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.
authors.affiliation: Eisai Co., Ltd , Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Okamoto
authors.affiliation: Eisai Co., Ltd , Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Ikemori-Kawada
authors.affiliation: Proteros Biostructures GmbH , Planegg-Martinsried, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Jestel
authors.affiliation: Proteros Biostructures GmbH , Planegg-Martinsried, Germany.
authors.forename: Konstanze
authors.initials: K
authors.lastname: von König
authors.affiliation: Eisai, Inc. , 4 Corporate Drive, Andover, Massachusetts 01810, United States.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Funahashi
authors.affiliation: Eisai Co., Ltd , Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Matsushima
authors.affiliation: Eisai Co., Ltd , Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Tsuruoka
authors.affiliation: Eisai Co., Ltd , Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Inoue
authors.affiliation: Eisai Co., Ltd , Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Matsui
keywords: Receptor tyrosine kinase; VEGFR2; X-ray crystallography; kinase inhibitor; kinetic interaction analysis