DFG-out Mode of Inhibition by an Irreversible Type‑1 Inhibitor Capable of Overcoming Gate-Keeper Mutations in FGF Receptors

Drug-resistance acquisition through kinase gate-keeper mutations is a major hurdle in the clinic. Here, we determined the first crystal structures of the human FGFR4 kinase domain (FGFR4K) alone and complexed with ponatinib, a promiscuous type-2 (DFG-out) kinase inhibitor, and an oncogenic FGFR4K ha...

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Bibliographic Details
Published in:ACS chemical biology 2015-01, Vol.10 (1), p.299-309
Main Authors: Huang, Zhifeng, Tan, Li, Wang, Huiyan, Liu, Yang, Blais, Steven, Deng, Jingjing, Neubert, Thomas A, Gray, Nathanael S, Li, Xiaokun, Mohammadi, Moosa
Format: Article
Language:English
Subjects:
Amino Acid Motifs
Animals
Cell Line
Cell Survival - drug effects
Crystallography, X-Ray
Drug Resistance, Neoplasm - drug effects
Drug Resistance, Neoplasm - genetics
Humans
Mice
Models, Molecular
Mutation
Oligopeptides - chemistry
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Receptor, Fibroblast Growth Factor, Type 4 - antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 4 - chemistry
Receptor, Fibroblast Growth Factor, Type 4 - genetics
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Tandem Mass Spectrometry
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Summary:Drug-resistance acquisition through kinase gate-keeper mutations is a major hurdle in the clinic. Here, we determined the first crystal structures of the human FGFR4 kinase domain (FGFR4K) alone and complexed with ponatinib, a promiscuous type-2 (DFG-out) kinase inhibitor, and an oncogenic FGFR4K harboring the V550L gate-keeper mutation bound to FIIN-2, a new type-1 irreversible inhibitor. Remarkably, like ponatinib, FIIN-2 also binds in the DFG-out mode despite lacking a functional group necessary to occupy the pocket vacated upon the DFG-out flip. Structural analysis reveals that the covalent bond between FIIN-2 and a cysteine, uniquely present in the glycine-rich loop of FGFR kinases, facilitates the DFG-out conformation, which together with the internal flexibility of FIIN-2 enables FIIN-2 to avoid the steric clash with the gate-keeper mutation that causes the ponatinib resistance. The structural data provide a blueprint for the development of next generation anticancer inhibitors through combining the salient inhibitory mechanisms of ponatinib and FIIN-2.
ISSN:1554-8929
1554-8937
DOI:10.1021/cb500674s