國家衛生研究院 NHRI:Item 3990099045/11849
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    jsp.display-item.identifier=請使用永久網址來引用或連結此文件: http://ir.nhri.org.tw/handle/3990099045/11849


    题名: Discovery of Conformational Control Inhibitors Switching off the Activated c-KIT and Targeting a Broad Range of Clinically Relevant c-KIT Mutants
    作者: Wu, TS;Lin, WH;Tsai, HJ;Hsueh, CC;Hsu, T;Wang, PC;Lin, HY;Peng, YH;Lu, CT;Lee, LC;Tu, CH;Kung, FC;Shiao, HY;Yeh, TK;Song, JS;Chang, JY;Su, YC;Chen, LT;Chen, CT;Jiaang, WT;Wu, SY
    贡献者: Institute of Biotechnology and Pharmaceutical Research;National Institute of Cancer Research
    摘要: Drug resistance due to acquired mutations that constitutively activate c-KIT is a significant challenge in the treatment of patients with gastrointestinal stromal tumors (GISTs). Herein, we identified 1-(5-ethyl-isoxazol-3-yl)-3-(4-{2-[6-(4-ethylpiperazin-1-yl)pyrimidin-4-ylamino]-thiazol-5-yl}phenyl)urea (10a) as a potent inhibitor against unactivated and activated c-KIT. The binding of 10a induced rearrangements of the DFG motif, αC-helix, juxtamembrane domain, and the activation loop to switch the activated c-KIT back to its structurally inactive state. To the best of our knowledge, it is the first structural evidence demonstrating how a compound can inhibit the activated c-KIT by switching back to its inactive state through a sequence of conformational changes. Moreover, 10a can effectively inhibit various c-KIT mutants and the proliferation of several GIST cell lines. The distinct binding features and superior inhibitory potency of 10a, together with its excellent efficacy in the xenograft model, establish 10a as worthy of further clinical evaluation in the advanced GISTs.
    日期: 2019-04-10
    關聯: Journal of Medicinal Chemistry. 2019 Apr 10;62(8):3940-3957.
    Link to: http://dx.doi.org/10.1021/acs.jmedchem.8b01845
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0022-2623&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000466053900009
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85064758026
    显示于类别:[伍素瑩] 期刊論文
    [蔣維棠] 期刊論文
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    [陳立宗] 期刊論文
    [蔡慧珍] 期刊論文

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