Development and Characterization of a Fluorescent Probe for GLS1 and the Application for High-Throughput Screening of Allosteric Inhibitors
| Autor: | Zhiyu Li, Jie Han, Lei Li, Zijian Kuang, Jubo Wang, Hong Ding, Hongyu Luan, Jinlei Bian, Ying Meng, Cheng Luo, Pengfei Xu, Xu Xi |
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| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
Glutaminase Chemistry Ligand binding assay High-throughput screening Allosteric regulation Serum Albumin Bovine 01 natural sciences 0104 chemical sciences High-Throughput Screening Assays 010404 medicinal & biomolecular chemistry 03 medical and health sciences Biochemistry Allosteric Regulation Cell Line Tumor Drug Discovery Click chemistry Molecular Medicine Humans Function (biology) Fluorescence anisotropy 030304 developmental biology Fluorescent Dyes |
| Zdroj: | Journal of medicinal chemistry. 62(21) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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