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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\u2005A (RgA). We demonstrate that RgA is a potent inhibitor of GLUT1 as well as GLUT3 and GLUT4, with an IC<jats:sub>50<\/jats:sub> value of low nanomolar for GLUT1. RgA was found to inhibit glucose uptake, leading to a decrease in cellular ATP synthesis, activation of AMP\u2010dependent kinase, inhibition of mTOR signaling, and induction of cell\u2010cycle arrest and apoptosis in cancer cells. Moreover, RgA was capable of inhibiting tumor xenografts in\u2005vivo without obvious side effects. RgA could thus be a new chemical tool to study GLUT function and a promising lead for developing anticancer drugs.<\/jats:p>","DOI":"10.1002\/anie.201905578","type":"journal-article","created":{"date-parts":[[2019,10,8]],"date-time":"2019-10-08T01:52:28Z","timestamp":1570499548000},"page":"17158-17162","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Discovery of a Potent GLUT Inhibitor from a Library of Rapafucins by Using 3D Microarrays"],"prefix":"10.1002","volume":"58","author":[{"given":"Zufeng","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Molecular Sciences The SJ Yan and HJ Mao Laboratory of Chemical Biology Johns Hopkins University School of Medicine  Room 516, Hunterian Building, 725 N. 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