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.
Current address: Department of Medicinal Chemistry, The University of Kansas, KS, USA.
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 IC 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.
葡萄糖转运蛋白在癌细胞增殖和存活中起着至关重要的作用，因此被视为有前途的癌症药物靶点。我们使用受天然产物雷帕霉素启发而合成的新型大环类化合物 rapafucin 的微阵列，筛选 GLUT1 的新型抑制剂。我们从 rapafucin 3D 微阵列中鉴定出多个命中化合物，并确认一个命中化合物是真正的 GLUT1 配体，我们将其命名为 rapaglutin A（RgA）。我们证明 RgA 是 GLUT1 以及 GLUT3 和 GLUT4 的有效抑制剂，对 GLUT1 的 IC 值为低纳摩尔。RgA 被发现可抑制葡萄糖摄取，导致细胞内 ATP 合成减少，激活 AMP 依赖的激酶，抑制 mTOR 信号，并诱导癌细胞周期停滞和凋亡。此外，RgA 能够在体内抑制肿瘤异种移植物，而没有明显的副作用。因此，RgA 可以成为研究 GLUT 功能的新化学工具，也是开发抗癌药物的有前途的先导化合物。
