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Publication Abstract from PubMed

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.

Distinct binding mode of multikinase inhibitor lenvatinib revealed by biochemical characterization.,Okamoto K, Ikemori-Kawada M, Jestel A, von Konig K, Funahashi Y, Matsushima T, Tsuruoka A, Inoue A, Matsui J ACS Med Chem Lett. 2014 Nov 17;6(1):89-94. doi: 10.1021/ml500394m. eCollection, 2015 Jan 8. PMID:25589937^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.