Structural Insights into FGFR Kinase Isoform Selectivity: Diverse Binding Modes of AZD4547 and Ponatinib in Complex with FGFR1 and FGFR4
Structural Insights into FGFR Kinase Isoform Selectivity: Diverse Binding Modes of AZD4547 and Ponatinib in Complex with FGFR1 and FGFR4
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DOI：
10.1016/j.str.2014.09.019
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发表时间：
2014-12-02
期刊：
影响因子：
5.7
通讯作者：
Norman, Richard A.
中科院分区：
文献类型：
--
作者：
Tucker, Julie A.;Klein, Tobias;Norman, Richard A.
成纤维细胞生长因子受体(FGFR)家族的受体酪氨酸激酶与多种癌症有关。尽管在ATP结合位点有很高的序列同源性，但大多数已报道的抑制剂对FGFR1-3亚型具有选择性，对FGFR4的效力大大降低，BCR-Abl抑制剂ponatinib是一个例外。在这里，我们给出了FGFR4激动域的晶体结构，并表明在与poatinib的复合体中，FGFR1和FGFR4激动域都采用DFG-out激活环构象。与候选药物AZD4547的FGFR1的结构进行比较，结合Ponatinib和AZD4547与FGFR1和FGFR4结合的动力学特征，揭示了观察到的选择性分布的差异，为开发FGFR4选择性抑制剂提供了理论基础。
The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases has been implicated in a wide variety of cancers. Despite a high level of sequence homology in the ATP-binding site, the majority of reported inhibitors are selective for the FGFR1-3 isoforms and display much reduced potency toward FGFR4, an exception being the Bcr-Abl inhibitor ponatinib. Here we present the crystal structure of the FGFR4 kinase domain and show that both FGFR1 and FGFR4 kinase domains in complex with ponatinib adopt a DFG-out activation loop conformation. Comparison with the structure of FGFR1 in complex with the candidate drug AZD4547, combined with kinetic characterization of the binding of ponatinib and AZD4547 to FGFR1 and FGFR4, sheds light on the observed differences in selectivity profiles and provides a rationale for developing FGFR4-selective inhibitors.