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Discovery of a Potent GLUT Inhibitor from a Library of Rapafucins by Using 3D Microarrays
Author(s) -
Guo Zufeng,
Cheng Zhiqiang,
Wang Jingxin,
Liu Wukun,
Peng Hanjing,
Wang Yuefan,
Rao A. V. Subba,
Li Ruojing,
Ying Xue,
Korangath Preethi,
Liberti Maria V.,
Li Yingjun,
Xie Yongmei,
Hong Sam Y.,
SchieneFischer Cordelia,
Fischer Gunter,
Locasale Jason W.,
Sukumar Saraswati,
Zhu Heng,
Liu Jun O.
Publication year - 2019
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201905578
Subject(s) - glut1 , glut3 , glucose transporter , pi3k/akt/mtor pathway , chemistry , cancer cell , in vivo , cancer , microarray , cell cycle , cell growth , cancer research , apoptosis , biology , biochemistry , gene , gene expression , genetics , endocrinology , insulin
Glucose transporters play an essential role in cancer cell proliferation and survival and have been pursued as promising cancer drug targets. Using microarrays of a library of new macrocycles known as rapafucins, which were inspired by the natural product rapamycin, we screened for new inhibitors of GLUT1. We identified multiple hits from the rapafucin 3D microarray and confirmed one hit as a bona fide GLUT1 ligand, which we named rapaglutin A (RgA). We demonstrate that RgA is a potent inhibitor of GLUT1 as well as GLUT3 and GLUT4, with an IC 50 value of low nanomolar for GLUT1. RgA was found to inhibit glucose uptake, leading to a decrease in cellular ATP synthesis, activation of AMP‐dependent kinase, inhibition of mTOR signaling, and induction of cell‐cycle arrest and apoptosis in cancer cells. Moreover, RgA was capable of inhibiting tumor xenografts in vivo without obvious side effects. RgA could thus be a new chemical tool to study GLUT function and a promising lead for developing anticancer drugs.