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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Cycle Checkpoints / drug effects
  • Drug Screening Assays, Antitumor
  • Glucose Transport Proteins, Facilitative / antagonists & inhibitors*
  • Humans
  • MCF-7 Cells
  • Macrolides / chemistry
  • Macrolides / pharmacology*
  • Molecular Structure
  • Phosphotransferases (Phosphate Group Acceptor) / metabolism
  • Protein Array Analysis
  • Signal Transduction
  • Sirolimus / chemistry
  • Small Molecule Libraries / chemistry*
  • Structure-Activity Relationship
  • TOR Serine-Threonine Kinases / metabolism
  • Tacrolimus / chemistry
  • Tacrolimus Binding Proteins


  • Antineoplastic Agents
  • Glucose Transport Proteins, Facilitative
  • Macrolides
  • Small Molecule Libraries
  • TOR Serine-Threonine Kinases
  • AMP-dependent kinase (ATP-forming)
  • Phosphotransferases (Phosphate Group Acceptor)
  • Tacrolimus Binding Proteins
  • Sirolimus
  • Tacrolimus