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Angew Chem Int Ed Engl. 2019 Nov 25;58(48):17158-17162. doi: 10.1002/anie.201905578. Epub 2019 Oct 31.

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

Author information

1
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. Wolfe Street, Baltimore, MD, USA.
2
Current address: Department of Medicinal Chemistry, The University of Kansas, KS, USA.
3
Current address: Institute of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
4
Current address: Food and Drug Administration, Silver Spring, MD, USA.
5
Current address: School of Pharmaceutical Sciences, Shihezi University, Shihezi, China.
6
Department of Oncology, Johns Hopkins University School of Medicine, USA.
7
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, USA.
8
Current address: Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
9
Current address: Rapafusyn Pharmaceuticals, Baltimore, MD, USA.
10
Department of Enzymology, Institute for Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, Germany.
11
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, USA.

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.

KEYWORDS:

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

PMID:
31591797
PMCID:
PMC6861656
[Available on 2020-11-25]
DOI:
10.1002/anie.201905578

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