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

• Published in: Angewandte Chemie International Edition Vol. 58; no. 48; pp. 17158 - 17162
• Main 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.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 25.11.2019
• Edition: International ed. in English
• Subjects: A549 Cells; AMP; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic drugs; Antitumor agents; antitumor compounds; Apoptosis; Apoptosis - drug effects; Cancer; Cell Cycle Checkpoints - drug effects; Cell proliferation; Cell survival; drug discovery; Drug Screening Assays, Antitumor; Glucose; Glucose Transport Proteins, Facilitative - antagonists & inhibitors; GLUT1; high-throughput screening; Humans; Inhibitors; Kinases; Macrolides - chemistry; Macrolides - pharmacology; MCF-7 Cells; Molecular Structure; Natural products; Organic chemistry; Phosphotransferases (Phosphate Group Acceptor) - metabolism; Protein Array Analysis; Rapamycin; Side effects; Signal Transduction; Sirolimus - chemistry; Small Molecule Libraries - chemistry; Structure-Activity Relationship; Tacrolimus - chemistry; Tacrolimus Binding Proteins; TOR protein; TOR Serine-Threonine Kinases - metabolism; Xenografts; Xenotransplantation; GLUT1; inhibitors; antitumor compounds; drug discovery; high-throughput screening
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.201905578

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. Rap sheet: A 3D small‐molecule microarray was developed and a library of 3918 macrocyclic rapafucins, which are inspired by the natural product rapamycin, was screened against the transmembrane protein human glucose transporter 1 (GLUT1) in cell lysate. A potent pan‐GLUT inhibitor, named rapaglutin A (RgA), was discovered. RgA was found to inhibit glucose uptake, induce cell apoptosis, and inhibit tumor xenografts in vivo.