國家衛生研究院 NHRI:Item 3990099045/11210
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    题名: Optimization of quinazoline-based kinase inhibitors: Identification of a dual FLT3/AURKA kinase inhibitor for the treatment of acute myeloid leukemia
    作者: Hsieh, HP;Hsu, YC;Ke, YY;Shiao, HY;Chang, CW;Lin, WH;Hsu, TA;Yeh, TK;Chen, CT
    贡献者: Institute of Biotechnology and Pharmaceutical Research
    摘要: AML is an aggressive and frequently fatal hematologic malignancy, which lacks for efficient therapeutics with tolerable side effects. We herein reported the design of novel kinase inhibitors as AURKA-selective, FLT3-selective, and dual AURKA/FLT3 inhibitors by fine-tuning appropriate substituent at certain positions of quinazoline-thiazole series. Further structure-activity relationship and computer modeling studies led to the identification of dual AURKA/FLT3 inhibitor 39 which exhibited both excellent enzyme activities (AURKA IC50 = 25 nM, FLT3 IC50 = 19 nM) as well as antiproliferative activities on MOLM-13 and MV4-11 cells, with an IC50 value of ~5 nM. More importantly, 39 potently inhibited AURKA and FLT3 exerted excellent in vivo efficacy not only in MOLM-13 but also MV4-11 xenograft models at a dose of 1 to 10 mg/kg, resulting in 39 as a preclinical development candidate with high potential for the treatment of AML.
    日期: 2015-08
    關聯: Abstracts of Papers of the American Chemical Society. 2015 Aug;250:Meeting Abstract 490.
    Link to: https://www.acs.org/content/acs/en/meetings/national-meeting/about/meetings-archive.html
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000432475701635
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