1415397-18-0Relevant articles and documents
Development and Characterization of a Fluorescent Probe for GLS1 and the Application for High-Throughput Screening of Allosteric Inhibitors
Xu, Xi,Kuang, Zijian,Han, Jie,Meng, Ying,Li, Lei,Luan, Hongyu,Xu, Pengfei,Wang, Jubo,Luo, Cheng,Ding, Hong,Li, Zhiyu,Bian, Jinlei
, p. 9642 - 9657 (2019)
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.
Novel 1,3,4-Selenadiazole-Containing Kidney-Type Glutaminase Inhibitors Showed Improved Cellular Uptake and Antitumor Activity
Chen, Zhao,Li, Di,Xu, Ning,Fang, Jinzhang,Yu, Yan,Hou, Wei,Ruan, Haoqiang,Zhu, Panpan,Ma, Renchao,Lu, Shiying,Cao, Danhui,Wu, Rui,Ni, Mowei,Zhang, Wei,Su, Weike,Ruan, Benfang Helen
, p. 589 - 603 (2019/01/10)
Kidney-type glutaminase [KGA/isoenzyme glutaminase C (GAC)] is becoming an important tumor metabolism target in cancer chemotherapy. Its allosteric inhibitor, CB839, showed early promise in cancer therapeutics but limited efficacy in in vivo cancer models. To improve the in vivo activity, we explored a bioisostere replacement of the sulfur atom in bis-2-(5-phenylacetamido-1,2,4-thiadiazol)ethyl sulfide and CB839 analogues with selenium using a novel synthesis of the selenadiazole moiety from carboxylic acids or nitriles. The resulting selenadiazole compounds showed enhanced KGA inhibition, more potent induction of reactive oxygen species, improved inhibition of cancer cells, and higher cellular and tumor accumulation than the corresponding sulfur-containing molecules. However, both CB839 and its selenium analogues show incomplete inhibition of the tested cancer cells, and a partial reduction in tumor size was observed in both the glutamine-dependent HCT116 and aggressive H22 liver cancer xenograft models. Despite this, tumor tissue damage and prolonged survival were observed in animals treated with the selenium analogue of CB839.
Design, synthesis, and pharmacological evaluation of bis-2-(5- phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3 (BPTES) analogs as glutaminase inhibitors
Shukla, Krupa,Ferraris, Dana V.,Thomas, Ajit G.,Stathis, Marigo,Duvall, Bridget,Delahanty, Greg,Alt, Jesse,Rais, Rana,Rojas, Camilo,Gao, Ping,Xiang, Yan,Dang, Chi V.,Slusher, Barbara S.,Tsukamoto, Takashi
, p. 10551 - 10563 (2013/02/22)
Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) is a potent and selective allosteric inhibitor of kidney-type glutaminase (GLS) that has served as a molecular probe to determine the therapeutic potential of GLS inhibition. In an attempt to identify more potent GLS inhibitors with improved drug-like molecular properties, a series of BPTES analogs were synthesized and evaluated. Our structure-activity relationship (SAR) studies revealed that some truncated analogs retained the potency of BPTES, presenting an opportunity to improve its aqueous solubility. One of the analogs, N-(5-{2-[2-(5-amino-[1,3,4] thiadiazol-2-yl)-ethylsulfanyl]-ethyl}-[1,3,4]thiadiazol-2-yl) -2-phenyl-acetamide 6, exhibited similar potency and better solubility relative to BPTES and attenuated the growth of P493 human lymphoma B cells in vitro as well as in a mouse xenograft model.
