國家衛生研究院 NHRI:Item 3990099045/13738
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    题名: Discovery of BPR1R024, an orally active and selective CSF1R inhibitor that exhibits antitumor and immunomodulatory activity in a murine colon tumor model
    作者: Lee, KH;Yen, WC;Lin, WH;Wang, PC;Lai, YL;Su, YC;Chang, CY;Wu, CS;Huang, YC;Yang, CM;Chou, LH;Yeh, TK;Chen, CT;Shih, C;Hsieh, HP
    贡献者: Institute of Biotechnology and Pharmaceutical Research
    摘要: Colony-stimulating factor-1 receptor (CSF1R) is implicated in tumor-associated macrophage (TAM) repolarization and has emerged as a promising target for cancer immunotherapy. Herein, we describe the discovery of orally active and selective CSF1R inhibitors by property-driven optimization of BPR1K871 (9), our clinical multitargeting kinase inhibitor. Molecular docking revealed an additional nonclassical hydrogen-bonding (NCHB) interaction between the unique 7-aminoquinazoline scaffold and the CSF1R hinge region, contributing to CSF1R potency enhancement. Structural studies of CSF1R and Aurora kinase B (AURB) demonstrated the differences in their back pockets, which inspired the use of a chain extension strategy to diminish the AURA/B activities. A lead compound BPR1R024 (12) exhibited potent CSF1R activity (IC50 = 0.53 nM) and specifically inhibited protumor M2-like macrophage survival with a minimal effect on antitumor M1-like macrophage growth. In vivo, oral administration of 12 mesylate delayed the MC38 murine colon tumor growth and reversed the immunosuppressive tumor microenvironment with the increased M1/M2 ratio.
    日期: 2021-10-14
    關聯: Journal of Medicinal Chemistry. 2021 Oct 14;64(19):14477-14497.
    Link to: http://dx.doi.org/10.1021/acs.jmedchem.1c01006
    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:000709633100028
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85117095471
    显示于类别:[謝興邦] 期刊論文
    [顏婉菁] 期刊論文
    [葉燈光] 期刊論文
    [陳炯東] 期刊論文
    [石全(2014-2017)] 期刊論文

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