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    Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/11849


    Title: Discovery of Conformational Control Inhibitors Switching off the Activated c-KIT and Targeting a Broad Range of Clinically Relevant c-KIT Mutants
    Authors: 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
    Contributors: Institute of Biotechnology and Pharmaceutical Research;National Institute of Cancer Research
    Abstract: 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.
    Date: 2019-04-10
    Relation: 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
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