A GLUT1 inhibitor-based fluorogenic probe for Warburg effect-targeted drug screening and diagnostic imaging of hyperglycolytic cancers.

Increased expression of glucose transporters, especially GLUT1 has been proven to be involved in the Warburg effect. Therefore, GLUT1-targeted oncological approaches are being successfully employed for clinical tumor diagnostic imaging (e.g. the 18F-FDG/PET), drug delivery and novel anticancer drug development. Despite the long history of the Warburg effect-targeted cancer diagnosis, other than antibody labeling, there have been no imaging tools developed for direct detection of the GLUT1 expression. Herein, we report the new strategy of using a non-antibody GLUT1 binding probe for Warburg effect-based tumor detection and diagnostic imaging. By specifically inhibits the transport function of GLUT1, the newly designed fluorescent probe, CUM-5, was found to be a useful tool not only for sensitive GLUT1-mediated cancer cell detection, but also for cell-based high-throughput GLUT inhibitor screening. In in vivo studies, CUM-5 shows clear advantages including desirable tumor-to-normal tissue contrast and excellent tumor selectivity (Tm/Bkg and Tm/Torg), as well as high fluorescence stability (long response time) and ideal physiological biocompatibility. In particular, the GLUT1 inhibitor probe offers the potential use for glycolysis-based diagnostic imaging in triple-negative breast cancer which is claimed to have unsatisfactory results with FDG/PET diagnosis, thus remaining a highly metastatic and lethal disease with a need for sensitive and precise identification.

Discovery of Nonpeptide, Reversible HER1/HER2 Dual-Targeting Small-Molecule Inhibitors as Near-Infrared Fluorescent Probes for Efficient Tumor Detection, Diagnostic Imaging, and Drug Screening.

The abnormal expression of epidermal growth factor receptors HER1(EGFR) and HER2 is strongly associated with cancer invasion, metastasis, and angiogenesis. Their molecular detection is mainly executed using genetically encoded or antibody-based diagnostic tracers, but no dual-targeting small-molecule bioprobe has been achieved. Here, we report the novel small-molecule fluorescent probes Cy3-AFTN and Cy5-AFTN as potent dual-targeting inhibitors for efficient detection of HER1/HER2 expression in cancer cells and in vivo tumor diagnostic imaging. Unlike the irreversible HER1/HER2 inhibitors, Cy3-AFTN and Cy5-AFTN were designed as reversible/noncovalent probes based on the clinical drug afatinib, by making the molecule structurally impossible for receptor-mediated Michael additions. The synthesized probes were validated with live cell fluorescence imaging, flow cytometry and confocal-mediated competitive binding inhibition, molecular docking study, and in vivo xenograft tumor detection. The probes are competitively replaceable by other HER1/HER2 inhibitors; thus, they are potentially useful in fluorometric high-throughput screening for drug discovery.