Small-molecule inhibitors of the c-Fes protein-tyrosine kinase.
Small-molecule inhibitors of the c-Fes protein-tyrosine kinase.
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DOI：
10.1016/j.chembiol.2012.01.020
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发表时间：
2012-04-20
影响因子：
--
通讯作者：
Smithgall TE
中科院分区：
文献类型：
--
作者：
Hellwig S;Miduturu CV;Kanda S;Zhang J;Filippakopoulos P;Salah E;Deng X;Choi HG;Zhou W;Hur W;Knapp S;Gray NS;Smithgall TE
c-Fes蛋白酪氨酸激酶调节支配分化、先天免疫应答和血管发生的细胞信号传导途径。在这里，我们报告的I型和II型激酶抑制剂的鉴定与有效的活性对c-Fes在体外和细胞为基础的测定。最有效的抑制剂之一是先前描述的间变性淋巴瘤激酶抑制剂，TAE 684。与c-Fes SH 2-激酶结构域复合的TAE 684的晶体结构显示出与ATP结合口袋的良好形状互补性，以及看门人甲硫氨酸在抑制机制中的关键作用。TAE 684和两种具有纳摩尔体外抗c-Fes效力的吡唑并嘧啶用于建立这种激酶在破骨细胞生成中的新作用，说明这些抑制剂作为工具化合物的价值，以探索与这种独特激酶相关的多种生物学功能。
The c-Fes protein-tyrosine kinase modulates cellular signaling pathways governing differentiation, the innate immune response, and vasculogenesis. Here we report the identification of Type I and II kinase inhibitors with potent activity against c-Fes both in vitro and in cell-based assays. One of the most potent inhibitors is the previously described anaplastic lymphoma kinase inhibitor, TAE684. The crystal structure of TAE684 in complex with the c-Fes SH2-kinase domain showed excellent shape complementarity with the ATP-binding pocket and a key role for the gatekeeper methionine in the inhibitory mechanism. TAE684 and two pyrazolopyrimidines with nanomolar potency against c-Fes in vitro were used to establish a novel role for this kinase in osteoclastogenesis, illustrating the value of these inhibitors as tool compounds to probe the diverse biological functions associated with this unique kinase.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
5.3
作者：
GREER, PA;MECKLINGHANSEN, K;PAWSON, T
通讯作者：
PAWSON, T
影响因子：
5.6
作者：
HUANG, CC;HAMMOND, C;BISHOP, JM
通讯作者：
BISHOP, JM
影响因子：
3.1
作者：
Kanda, Shigeru;Miyata, Yasuyoshi
通讯作者：
Miyata, Yasuyoshi
影响因子：
5.2
作者：
Kanda, Shigeru;Miyata, Yasuyoshi;Smithgall, Thomas E.
通讯作者：
Smithgall, Thomas E.