Discovery of a Potent GLUT Inhibitor from a Library of Rapafucins by Using 3D Microarrays
Year: 2019
Type: article
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
Institutions: Johns Hopkins University, Johns Hopkins Medicine, University of Kansas, Nanjing University of Chinese Medicine, United States Food and Drug Administration, Shihezi University, Duke University, Duke Medical Center, Sichuan University, West China Medical Center of Sichuan University, West China Hospital of Sichuan University, Martin Luther University Halle-Wittenberg
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
Awards: G1165598027, G5547113124
OpenAlex ID: W2979809114