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ACS Med Chem Lett. 2014 Nov 17;6(1):89-94. doi: 10.1021/ml500394m. eCollection 2015 Jan 8.

Distinct binding mode of multikinase inhibitor lenvatinib revealed by biochemical characterization.

Author information

1
Eisai Co., Ltd , Tsukuba, Ibaraki 300-2635, Japan.
2
Proteros Biostructures GmbH , Planegg-Martinsried, Germany.
3
Eisai, Inc. , 4 Corporate Drive, Andover, Massachusetts 01810, United States.

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.

KEYWORDS:

Receptor tyrosine kinase; VEGFR2; X-ray crystallography; kinase inhibitor; kinetic interaction analysis

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