A development of chimeric VEGFR2 TK inhibitor based on two ligand conformers from PDB: 1Y6A complex - Medicinal chemistry consequences of a TKs analysis

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• 作者：Lucia Lintnerov谩 ; Melissa Garc铆a-Caballero ; Fridrich Greg谩艌 ; Milan Melicher膷铆k ; Ana R. Quesada ; Juraj Dobia拧 ; J谩n L谩c ; Marta Sali拧ov谩 ; Andrej Boh谩膷
• 关键词：Angiogenesis sorafenib Nexavar sunitinib Sutent oxazole ; Properties of VEGFR-2 tyrosine kinase variants ; Flexible tyrosine kinase activation loop ; Type I inhibitor DFG-out A-loop/ligand collision ; Medicinal chemistry consequences
• 刊名：European Journal of Medicinal Chemistry
• 出版年：24 January, 2014
• 年：2014
• 卷：72
• 期：Complete
• 页码：146-159
• 全文大小：2702 K

文摘

VEGFR2 is an important mediator of angiogenesis and influences fate of some cancer stem cells. Here we analysed all 34 structures of VEGFR2 TK available from PDB database. From them a complex PDB: has an exceptional AAZ ligand bound to TK in form of two conformers (U- and S-shaped). This observation inspired us to develop three chimeric bispyridyl VEGFR2 inhibitors by combining structural features of both AAZ conformers and/or their relative ligand AAX (PDB: 1Y6B).

Our most interesting inhibitor 22SYM has an enzymatic VEGFR2 TK activity (IC₅₀: 15.1聽nM) comparable or better to the active compounds from clinical drugs Nexavar and Sutent. 22SYM inhibits growth, migration and tube formation of endothelial cells (EC) and selectively induces EC apoptosis. 22SYM also inhibits in聽vivo angiogenesis in Zebrafish embryo assay.

Additionally to the above results, we proved here that tyrosine kinases in an inactive form possessing Type I inhibitors can adopt both a closed or an opened conformation of kinase A-loop independently on their DFG-out arrangement. We proposed here that an activity of certain Type I inhibitors (e.g. 22SYM-like) in complex with DFG-out TK can be negatively influenced by collisions with a dynamically moving TK A-loop.