國家衛生研究院 NHRI:Item 3990099045/3611
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    题名: Structure-based drug design of novel aurora kinase a inhibitors: Structural basis for potency and specificity
    作者: Coumar, MS;Leou, JS;Shukla, P;Wu, JS;Dixit, AK;Lin, WH;Chang, CY;Lien, TW;Tan, UK;Chen, CH;Hsu, JTA;Chao, YS;Wu, SY;Hsieh, HP
    贡献者: Division of Biotechnology and Pharmaceutical Research
    摘要: Aurora kinases have emerged as attractive targets for the design of anticancer drugs. Through structure- based virtual screening, novel pyrazole hit 8a was identified as Aurora kinase A inhibitor (IC50 = 15.1 μM). X-ray cocrystal structure of 8a in complex with Aurora A protein revealed the C-4 position ethyl carboxylate side chain as a possible modification site for improving the potency. On the basis of this insight, bioisosteric replacement of the ester with amide linkage and changing the ethyl substituent to hydrophobic 3-acetami- dophenyl ring led to the identification of 12w with a ~450-fold improved Aurora kinase A inhibition potency (lC50 = 33 nM), compared to 8a. Compound 12w showed selective inhibition of Aurora A kinase over Aurora B/C, which might be due to the presence of a unique H-bond interaction between the 3-acetamido group and the Aurora A nonconserved Thr217 residue, which in Aurora B/C is Glu and found to sterically clash with the 3-acetamido group in modeling studies.
    日期: 2009-02-26
    關聯: Journal of Medicinal Chemistry. 2009 Feb 26;52(4):1050-1062.
    Link to: http://dx.doi.org/10.1021/jm801270e
    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:000263530200017
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=64349120831
    显示于类别:[謝興邦] 期刊論文
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    [趙宇生(2002-2013)] 期刊論文
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