國家衛生研究院 NHRI:Item 3990099045/13542
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    题名: Design and synthesis of novel orally selective and type II pan-TRK inhibitors to overcome mutations by property-driven optimization
    作者: Li, MC;Lin, WH;Wang, PC;Su, YC;Chen, PY;Fan, CM;Chen, CP;Huang, CL;Chiu, CH;Chang, L;Chen, CT;Yeh, TK;Hsieh, HP
    贡献者: Institute of Biotechnology and Pharmaceutical Research
    摘要: Rare oncogenic NTRK gene fusions result in uncontrolled TRK signaling leading to various adult and pediatric solid tumors. Based on the architecture of our multi-targeted clinical candidate BPR1K871 (10), we designed and synthesized a series of quinazoline compounds as selective and orally bioavailable type II TRK inhibitors. Property-driven and lead optimization strategies informed by structure-activity relationship studies led to the identification of 39, which showed higher (about 15-fold) selectivity for TRKA over AURA and AURB, as well as potent cellular activity (IC(50) = 56.4 nM) against the KM12 human colorectal cancer cell line. 39 also displayed good AUC and oral bioavailability (F = 27%), excellent in vivo efficacy (TGI = 64%) in a KM12 xenograft model, and broad-spectrum anti-TRK mutant potency (IC(50) = 3.74-151.4 nM), especially in the double-mutant TRKA enzymatic assays. 39 is therefore proposed for further development as a next-generation, selective, and orally-administered type II TRK inhibitor.
    日期: 2021-11-15
    關聯: European Journal of Medicinal Chemistry. 2021 Nov 15;224:Article number 113673.
    Link to: http://dx.doi.org/10.1016/j.ejmech.2021.113673
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0223-5234&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000703110000005
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85111854736
    显示于类别:[謝興邦] 期刊論文
    [葉燈光] 期刊論文
    [陳炯東] 期刊論文

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