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

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.

• Authors: 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
• Journal: Angewandte Chemie (International ed. in English) (Angew Chem Int Ed Engl) Vol. 58 Issue 48 Pg. 17158-17162 (11 25 2019) ISSN: 1521-3773 [Electronic] Germany
• PMID: 31591797 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• 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

Topics

• A549 Cells
• Antineoplastic Agents (chemistry, 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, 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