Novel Hypoxia-specific Radiosensitizers Designed for GLUT-mediated Transport into Hypoxic Cells

The objective of this research is to develop new drugs that will have theranostic (diagnostic and therapeutic) applications in cancer management. Fostering a new class of radiosensitizing anticancer drugs that will undergo... [ view full abstract ]

The objective of this research is to develop new drugs that will have theranostic (diagnostic and therapeutic) applications in cancer management. Fostering a new class of radiosensitizing anticancer drugs that will undergo facilitated transport into hypoxic cells adds a unique dimension to this theranostic approach. Our immediate goal is to test and model the interactions of azomycin (AZ; 2-nitroimidazole) glucose adducts with transmembrane glucose transporter proteins (GLUTs), in order to theranostically exploit the upregulated expression of GLUTs in hypoxic cells.
Candidate compounds feature a bioreductive unit (AZ) to promote hypoxia-selective binding and radiosensitization, a transport moiety (glucose) to facilitate transport by GLUTs and a molecular linker, which can be radiolabeled or otherwise modified to provide diagnostic and therapeutic properties. Experimental quantification of the ability of this new glucose adducts to compete with glucose for GLUT-mediated transport into cancer cells is now reported. The aim is to create experimental structure-activity correlations (SAC), and to compare these experimental SAC data to in silico GLUT-substrate affinity data generated by molecular docking, to support a better understanding of the cell membrane interactions of these innovative, bioreductively-activated glucose adducts. In silico docking of the synthesized compounds on a model of the bacterial homologue of GLUT1-4 was performed using AutoDock Vina. Some of the initial docking and experimental results will be presented in the poster.