國家衛生研究院 NHRI:Item 3990099045/12552
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    题名: Drug-like property optimization: Discovery of orally bioavailable quinazoline-based multi-targeted kinase inhibitors
    作者: Lin, SY;Chang, CF;Coumar, MS;Chen, PY;Kuo, FM;Chen, CH;Li, MC;Lin, WH;Kuo, PC;Wang, SY;Li, AS;Lin, CY;Yang, CM;Yeh, TK;Song, JS;Hsu, JTA;Hsieh, HP
    贡献者: Institute of Biotechnology and Pharmaceutical Research
    摘要: In an effort to develop new cancer therapeutics, we have reported clinical candidate BPR1K871 (1) as a potentanticancercompound in MOLM-13 and MV4-11 leukemia models, as well as in colorectal and pancreatic animal models. As BPR1K871 lacks oral bioavailability, we continued searching for orally bioavailable analogs through drug-like property optimization. We optimized both the physicochemical properties (PCP) as well as in vitro rat liver microsomal stability of 1, with concomitant monitoring of aurora kinase enzyme inhibition as well as cellular anti-proliferative activity in HCT-116 cell line. Structural modification at the 6- and 7-position of quinazoline core of 1 led to the identification of 34 as an orally bioavailable (F% = 54) multi-kinase inhibitor, which exhibits potent anti-proliferative activity against various cancer cell lines. Quinazoline 34 is selected as a promising oral lead candidate for further preclinical evaluation.
    日期: 2020-05
    關聯: Bioorganic Chemistry. 2020 May;98:Article number 103689.
    Link to: http://dx.doi.org/10.1016/j.bioorg.2020.103689
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0045-2068&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000526784800021
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85081243886
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