國家衛生研究院 NHRI:Item 3990099045/10084
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    题名: Discovery of BPR1K871, a quinazoline based, multi-kinase inhibitor for the treatment of AML and solid tumors: Rational design, synthesis, in vitro and in vivo evaluation
    作者: Chang Hsu, Y;Selvaraj Coumar, M;Wang, WC;Shiao, HY;Ke, YY;Lin, WH;Kuo, CC;Chang, CW;Kuo, FM;Chen, PY;Wang, SY;Li, AS;Chen, CH;Kuo, PC;Chen, CP;Wu, MH;Huang, CL;Yen, KJ;Chang, YI;Hsu, JT;Chen, CT;Yeh, TK;Song, JS;Shih, C;Hsieh, HP
    贡献者: Institute of Biotechnology and Pharmaceutical Research
    摘要: The design and synthesis of a quinazoline-based, multi-kinase inhibitor for the treatment of acute myeloid leukemia (AML) and other malignancies is reported. Based on the previously reported furanopyrimidine 3, quinazoline core containing lead 4 was synthesized and found to impart dual FLT3/AURKA inhibition (IC50 = 127/5 nM), as well as improved physicochemical properties. A detailed structure-activity relationship study of the lead 4 allowed FLT3 and AURKA inhibition to be finely tuned, resulting in AURKA selective (5 and 7; 100-fold selective over FLT3), FLT3 selective (13; 30-fold selective over AURKA) and dual FLT3/AURKA selective (BPR1K871; IC50 = 19/22 nM) agents. BPR1K871 showed potent anti-proliferative activities in MOLM-13 and MV4-11 AML cells (EC50 ~ 5 nM). Moreover, kinase profiling and cell-line profiling revealed BPR1K871 to be a potential multi-kinase inhibitor. Functional studies using western blot and DNA content analysis in MV4-11 and HCT-116 cell lines revealed FLT3 and AURKA/B target modulation inside the cells. In vivo efficacy in AML xenograft models (MOLM-13 and MV4-11), as well as in solid tumor models (COLO205 and Mia-PaCa2), led to the selection of BPR1K871 as a preclinical development candidate for anti-cancer therapy. Further detailed studies could help to investigate the full potential of BPR1K871 as a multi-kinase inhibitor.
    日期: 2016-12
    關聯: Oncotarget. 2016 Dec;7(52):86239-86256.
    Link to: http://dx.doi.org/10.18632/oncotarget.13369
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000391422500047
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85007494556
    显示于类别:[謝興邦] 期刊論文
    [石全(2014-2017)] 期刊論文
    [葉燈光] 期刊論文
    [陳炯東] 期刊論文
    [郭靜娟] 期刊論文
    [徐祖安] 期刊論文
    [王文傑] 期刊論文

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