Discovery of a Potent GLUT Inhibitor from a Library of Rapafucins by Using 3D Microarrays. (31st October 2019)

• Record Type: Journal Article
• Authors: Guo, Zufeng; Cheng, Zhiqiang; Wang, Jingxin; Liu, Wukun; Peng, Hanjing; Wang, Yuefan; Rao, A. V. Subba; Li, Ruo‐jing; Ying, Xue; Korangath, Preethi; Liberti, Maria V.; Li, Yingjun; Xie, Yongmei; Hong, Sam Y.; Schiene‐Fischer, Cordelia; Fischer, Gunter; Locasale, Jason W.; Sukumar, Saraswati; Zhu, Heng; Liu, Jun O.
• Is Part Of: Angewandte Chemie. Volume 131:Number 48(2019)
• Page Start: 17318
• Page End: 17322
• Publication Date: 2019-10-31
• Subjects: Tumortherapeutika -- Wirkstoffentwicklung -- GLUT1 -- Inhibitoren -- Hochdurchsatz-Screening; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201905578
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: 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 IC50 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. Abstract : Ein 3D‐Mikroarray wurde entwickelt und zum Screening einer Bibliothek von 3918 makrocyclischen Rapafucinen gegen das transmembranäre Protein Humanglukosetransporter 1 (GLUT1) in Zelllysat eingesetzt. Ein potenter Pan‐GLUT‐Inhibitor, Rapaglutin A (RgA), wurde entdeckt, der die Glukoseaufnahme hemmt, Zellapoptose verursacht und Tumor‐Xenografts in vivo inhibiert.