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首页> 外文期刊>Journal of Medicinal Chemistry >Development and Characterization of a Fluorescent Probe for GLS1 and the Application for High-Throughput Screening of Allosteric Inhibitors
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Development and Characterization of a Fluorescent Probe for GLS1 and the Application for High-Throughput Screening of Allosteric Inhibitors

机译：对GLS1荧光探针的开发和表征及颠覆性抑制剂的高通量筛选应用

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摘要

Glutaminase (GLS1) is a cancer energy metabolism protein which plays a predominant role in cell growth and proliferation. Because of its major involvement in malignant tumor, small-molecule GLS1 inhibitors are urgently needed to assess its therapeutic potential and for probing their underlying biology function. Recent studies showed that targeting the allosteric binding site represented a promising strategy for identifying potent and selective GLS1 inhibitors. Herein, we present the synthesis of two fluorescent probes targeting the allosteric binding site of GLS1 and their usage as mechanistic tools in multiple applicable assay platform. The fluorescence polarization (FP)-based binding assay enables easy, fast, and reliable screen of allosteric inhibitors from our in-house compound library obtained through click chemistry method. The obtained compound C147 (named as CPU-L1) has been proved to be more potent and with greater solubility than the control compound CB839, which could serve as promising leads for further optimization as novel GLS1 inhibitors.
机译：谷氨酰胺酶（GLS1）是一种癌症能量代谢蛋白，其在细胞生长和增殖中起主要作用。因为在恶性肿瘤其主要参与的，迫切需要小分子抑制剂GLS1评估其治疗潜力和用于探测其基本生物学功能。最近的研究表明，靶向颠覆结合位点代表了鉴定有效和选择性GLS1抑制剂的有希望的策略。在此，我们介绍了靶向GLS1的变构结合位点的两种荧光探针及其用作多种适用的测定平台中的机械工具。基于咔哒化化学方法获得的荧光偏振（FP）的结合测定能够容易，快速，快速，快速，可靠的囊性抑制剂筛选，通过咔哒化学方法获得。已得到的化合物C147（命名为CPU-L1）已经被证明是更有效的并且具有比对照化合物CB839更大的溶解度，其可以作为进一步优化作为新型GLS1抑制剂的有前途的引线。

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  • 来源
    《Journal of Medicinal Chemistry》 |2019年第21期|共16页
  • 作者

    Xu Xi; Kuang Zijian; Han Jie; Meng Ying; Li Lei; Luan Hongyu; Xu Pengfei; Wang Jubo; Luo Cheng; Ding Hong; Li Zhiyu; Bian Jinlei;

  • 作者单位

    China Pharmaceut Univ Sch Pharm Dept Med Chem Jiangsu Key Lab Drug Design &

    Optimizat Tongjiaxiang 24 Nanjing 210009 Jiangsu Peoples R China;

    China Pharmaceut Univ Sch Pharm Dept Med Chem Jiangsu Key Lab Drug Design &

    Optimizat Tongjiaxiang 24 Nanjing 210009 Jiangsu Peoples R China;

    Chinese Acad Sci Shanghai Inst Materia Med State Key Lab Drug Res CAS Key Lab Receptor Res 555 Zuchongzhi Rd Shanghai 201203 Peoples R China;

    China Pharmaceut Univ Sch Pharm Dept Med Chem Jiangsu Key Lab Drug Design &

    Optimizat Tongjiaxiang 24 Nanjing 210009 Jiangsu Peoples R China;

    China Pharmaceut Univ Sch Pharm Dept Med Chem Jiangsu Key Lab Drug Design &

    Optimizat Tongjiaxiang 24 Nanjing 210009 Jiangsu Peoples R China;

    China Pharmaceut Univ Sch Pharm Dept Med Chem Jiangsu Key Lab Drug Design &

    Optimizat Tongjiaxiang 24 Nanjing 210009 Jiangsu Peoples R China;

    China Pharmaceut Univ Sch Pharm Dept Med Chem Jiangsu Key Lab Drug Design &

    Optimizat Tongjiaxiang 24 Nanjing 210009 Jiangsu Peoples R China;

    China Pharmaceut Univ Sch Pharm Dept Med Chem Jiangsu Key Lab Drug Design &

    Optimizat Tongjiaxiang 24 Nanjing 210009 Jiangsu Peoples R China;

    Chinese Acad Sci Shanghai Inst Materia Med State Key Lab Drug Res CAS Key Lab Receptor Res 555 Zuchongzhi Rd Shanghai 201203 Peoples R China;

    Chinese Acad Sci Shanghai Inst Materia Med State Key Lab Drug Res CAS Key Lab Receptor Res 555 Zuchongzhi Rd Shanghai 201203 Peoples R China;

    China Pharmaceut Univ Sch Pharm Dept Med Chem Jiangsu Key Lab Drug Design &

    Optimizat Tongjiaxiang 24 Nanjing 210009 Jiangsu Peoples R China;

    China Pharmaceut Univ Sch Pharm Dept Med Chem Jiangsu Key Lab Drug Design &

    Optimizat Tongjiaxiang 24 Nanjing 210009 Jiangsu Peoples R China;

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  • 正文语种 eng
  • 中图分类 药学;
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