Rana Natasha, Aziz Marwa A, Oraby Ahmed K, Wuest Melinda, Dufour Jennifer, Abouzid Khaled A M, Wuest Frank, West F G
Department of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada.
Department of Oncology, University of Alberta-Cross Cancer Institute, Edmonton, AB T6G IZ2, Canada.
Pharmaceutics. 2022 Apr 10;14(4):828. doi: 10.3390/pharmaceutics14040828.
Deregulation and changes in energy metabolism are emergent and important biomarkers of cancer cells. The uptake of hexoses in cancer cells is mediated by a family of facilitative hexose membrane-transporter proteins known as Glucose Transporters (GLUTs). In the clinic, numerous breast cancers do not show elevated glucose metabolism (which is mediated mainly through the GLUT1 transporter) and may use fructose as an alternative energy source. The principal fructose transporter in most cancer cells is GLUT5, and its mRNA was shown to be elevated in human breast cancer. This offers an alternative strategy for early detection using fructose analogs. In order to selectively scout GLUT5 binding-pocket requirements, we designed, synthesized and screened a new class of fructose mimics based upon the 2,5-anhydromannitol scaffold. Several of these compounds display low millimolar IC values against the known high-affinity F-labeled fructose-based probe 6-deoxy-6-fluoro-D-fructose (6-FDF) in murine EMT6 breast cancer cells. In addition, this work used molecular docking and molecular dynamics simulations (MD) with previously reported GLUT5 structures to gain better insight into hexose-GLUT interactions with selected ligands governing their preference for GLUT5 compared to other GLUTs. The improved inhibition of these compounds, and the refined model for their binding, set the stage for the development of high-affinity molecular imaging probes targeting cancers that express the GLUT5 biomarker.
能量代谢的失调和变化是癌细胞新出现的重要生物标志物。癌细胞中己糖的摄取是由一类易化性己糖膜转运蛋白介导的，这类蛋白被称为葡萄糖转运蛋白（GLUTs）。在临床上，许多乳腺癌并未表现出葡萄糖代谢升高（主要通过GLUT1转运蛋白介导），可能会将果糖用作替代能源。大多数癌细胞中的主要果糖转运蛋白是GLUT5，其mRNA在人类乳腺癌中显示升高。这为使用果糖类似物进行早期检测提供了一种替代策略。为了选择性地探究GLUT5结合口袋的需求，我们基于2,5-脱水甘露糖醇支架设计、合成并筛选了一类新的果糖模拟物。其中几种化合物在小鼠EMT6乳腺癌细胞中，对已知的高亲和力F标记的基于果糖的探针6-脱氧-6-氟-D-果糖（6-FDF）显示出低毫摩尔级的IC值。此外，这项工作利用分子对接和分子动力学模拟（MD）以及先前报道的GLUT5结构，以便更好地了解己糖与GLUT的相互作用，以及与选定配体相比，这些配体对GLUT5的偏好，而不是其他GLUTs。这些化合物的抑制作用得到改善，以及它们结合的精细模型，为开发靶向表达GLUT5生物标志物的癌症的高亲和力分子成像探针奠定了基础。
