Discovery of a Potent GLUT Inhibitor from a Library of Rapafucins by Using 3D Microarrays

Zufeng Guo, Zhiqiang Cheng, Jingxin Wang, Wukun Liu, Hanjing Peng, Yuefan Wang, A. V.Subba Rao, Ruo jing Li, Xue Ying, Preethi Korangath, Maria V. Liberti, Yingjun Li, Yongmei Xie, Sam Y. Hong, Cordelia Schiene-Fischer, Gunter Fischer, Jason W. Locasale, Saraswati Sukumar, Heng Zhu, Jun O. Liu

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)17158-17162
Number of pages5
JournalAngewandte Chemie - International Edition
Volume58
Issue number48
DOIs
StatePublished - Nov 25 2019

Keywords

  • GLUT1
  • antitumor compounds
  • drug discovery
  • high-throughput screening
  • inhibitors

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

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  • Cite this

    Guo, Z., Cheng, Z., Wang, J., Liu, W., Peng, H., Wang, Y., Rao, A. V. S., Li, R. J., Ying, X., Korangath, P., Liberti, M. V., Li, Y., Xie, Y., Hong, S. Y., Schiene-Fischer, C., Fischer, G., Locasale, J. W., Sukumar, S., Zhu, H., & Liu, J. O. (2019). Discovery of a Potent GLUT Inhibitor from a Library of Rapafucins by Using 3D Microarrays. Angewandte Chemie - International Edition, 58(48), 17158-17162. https://doi.org/10.1002/anie.201905578