Design, synthesis, and evaluation of positron emission tomography/fluorescence dual imaging probes for targeting facilitated glucose transporter 1 (GLUT1)

2021 ◽  
Vol 19 (14) ◽  
pp. 3241-3254
Author(s):  
Richard Yuen ◽  
Michael Wagner ◽  
Susan Richter ◽  
Jennifer Dufour ◽  
Melinda Wuest ◽  
...  
Keyword(s):  
Breast Cancer Cells ◽  
Glucose Transporter ◽  
Fluorescent Imaging ◽  
Hexose Transporter ◽  
Design Synthesis ◽  
Glucose Transporter 1 ◽  
Positron Emission ◽  
Imaging Probes ◽  
Dual Imaging ◽  
Transporter Glut1

We describe the synthesis and analysis of novel different glucose-based dual probes for tandem PET and fluorescent imaging of facilitated hexose transporter GLUT1 in breast cancer cells.

scholarly journals Orthosteric-allosteric dual inhibitors of PfHT1 as selective anti-malarial agents

2020 ◽  
Author(s):  
Jian Huang ◽  
Yafei Yuan ◽  
Na Zhao ◽  
Debing Pu ◽  
Qingxuan Tang ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Rational Design ◽  
Glucose Transporter ◽  
Blood Stage ◽  
Host Cells ◽  
Sugar Uptake ◽  
Hexose Transporter ◽  
Next Generation ◽  
Malaria Parasites ◽  
Glucose Transporter 1

AbstractArtemisinin-resistant malaria parasites have emerged and been spreading, posing a significant public health challenge. Anti-malarial drugs with novel mechanisms of action are therefore urgently needed. In this report, we exploit a “selective starvation” strategy by selectively inhibiting Plasmodium falciparum hexose transporter 1 (PfHT1), the sole hexose transporter in Plasmodium falciparum, over human glucose transporter 1 (hGLUT1), providing an alternative approach to fight against multidrug-resistant malaria parasites. Comparison of the crystal structures of human GLUT3 and PfHT1 bound to C3361, a PfHT1-specific moderate inhibitor, revealed an inhibitor binding-induced pocket that presented a promising druggable site. We thereby designed small-molecules to simultaneously block the orthosteric and allosteric pockets of PfHT1. Through extensive structure-activity relationship (SAR) studies, the TH-PF series was identified to selectively inhibit PfHT1 over GLUT1 and potent against multiple strains of the blood-stage P. falciparum. Our findings shed light on the next-generation chemotherapeutics with a paradigm-shifting structure-based design strategy to simultaneously targeting the orthosteric and allosteric sites of a transporter.Significance statementBlocking sugar uptake in P. falciparum by selectively inhibiting the hexose transporter PfHT1 kills the blood-stage parasites without affecting the host cells, indicating PfHT1 as a promising therapeutic target. Here, we report the development of novel small-molecule inhibitors that are selectively potent to the malaria parasites over human cell lines by simultaneously targeting the orthosteric and the allosteric binding sites of PfHT1. Our findings established the basis for the rational design of next-generation anti-malarial drugs.

scholarly journals Orthosteric–allosteric dual inhibitors of PfHT1 as selective antimalarial agents

2021 ◽  
Vol 118 (3) ◽  
pp. e2017749118
Author(s):  
Jian Huang ◽  
Yafei Yuan ◽  
Na Zhao ◽  
Debing Pu ◽  
Qingxuan Tang ◽  
...  
Keyword(s):  
Glucose Transporter ◽  
Sequence Similarity ◽  
Specific Inhibitor ◽  
Multidrug Resistant ◽  
Hexose Transporter ◽  
Malaria Parasites ◽  
Glucose Transporter 1 ◽  
Allosteric Sites ◽  
Significant Public Health ◽  
Multiple Strains

Artemisinin-resistant malaria parasites have emerged and have been spreading, posing a significant public health challenge. Antimalarial drugs with novel mechanisms of action are therefore urgently needed. In this report, we exploit a “selective starvation” strategy by inhibiting Plasmodium falciparum hexose transporter 1 (PfHT1), the sole hexose transporter in P. falciparum, over human glucose transporter 1 (hGLUT1), providing an alternative approach to fight against multidrug-resistant malaria parasites. The crystal structure of hGLUT3, which shares 80% sequence similarity with hGLUT1, was resolved in complex with C3361, a moderate PfHT1-specific inhibitor, at 2.3-Å resolution. Structural comparison between the present hGLUT3-C3361 and our previously reported PfHT1-C3361 confirmed the unique inhibitor binding-induced pocket in PfHT1. We then designed small molecules to simultaneously block the orthosteric and allosteric pockets of PfHT1. Through extensive structure–activity relationship studies, the TH-PF series was identified to selectively inhibit PfHT1 over hGLUT1 and potent against multiple strains of the blood-stage P. falciparum. Our findings shed light on the next-generation chemotherapeutics with a paradigm-shifting structure-based design strategy to simultaneously target the orthosteric and allosteric sites of a transporter.

scholarly journals The pan-deacetylase inhibitor panobinostat induces cell death and synergizes with everolimus in Hodgkin lymphoma cell lines

Blood ◽  
2012 ◽  
Vol 119 (17) ◽  
pp. 4017-4025 ◽  
Author(s):  
Manuela Lemoine ◽  
Enrico Derenzini ◽  
Daniela Buglio ◽  
L. Jeffrey Medeiros ◽  
R. Eric Davis ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Glucose Transporter ◽  
Mammalian Target Of Rapamycin ◽  
Hypoxia Inducible Factor ◽  
Mtor Inhibitors ◽  
Clinical Activity ◽  
Glucose Transporter 1 ◽  
Positron Emission ◽  
Deacetylase Inhibitor

AbstractThe pan-deacetylase inhibitor panobinostat (LBH589) recently has been shown to have significant clinical activity in patients with relapsed Hodgkin lymphoma, but its mechanism of action in Hodgkin lymphoma remains unknown. In this study, we demonstrate that panobinostat has potent antiproliferative activity against Hodgkin lymphoma–derived cell lines. At the molecular level, panobinostat activated the caspase pathway, inhibited STAT5 and STAT6 phosphorylation, and down-regulated hypoxia-inducible factor 1 α and its downstream targets, glucose transporter 1 (GLUT1) and vascular endothelial growth factor. Paradoxically, panobinostat inhibited LKB1 and AMP-activated protein kinase, leading to activation of mammalian target of rapamycin (mTOR) that promotes survival. Combining panobinostat with the mTOR inhibitor everolimus (RAD001) inhibited panobinostat-induced mTOR activation and enhanced panobinostat antiproliferative effects. Collectively, our data demonstrate that panobinostat is a potent deacetylase inhibitor against Hodgkin lymphoma–derived cell lines, and provide a mechanistic rationale for combining panobinostat with mTOR inhibitors for treating Hodgkin lymphoma patients. Furthermore, the effect of panobinostat on GLUT1 expression suggests that panobinostat may modulate the results of clinical diagnostic imaging tests that depend of functional GLUT1, such as fluorodeoxyglucose positron emission tomography.

scholarly journals Expression of GLUT-1 and GLUT-3 in Xanthogranulomatous Cholecystitis Induced a Positive Result on 18F-FDG PET: Report of a Case

2013 ◽  
Vol 98 (4) ◽  
pp. 372-378 ◽  
Author(s):  
Shigeaki Sawada ◽  
Yutaka Shimada ◽  
Shinichi Sekine ◽  
Kazuto Shibuya ◽  
Isaku Yoshioka ◽  
...  
Keyword(s):  
Positive Result ◽  
Fdg Pet ◽  
Glucose Transporter ◽  
Inflammatory Cells ◽  
Gallbladder Wall ◽  
Xanthogranulomatous Cholecystitis ◽  
Glucose Transporter 1 ◽  
Glut 1 ◽  
Positron Emission ◽  
18F Fdg

Abstract Although several reports have revealed that fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET) is useful for differentiating between benign and malignant lesions in the gallbladder, the positive results of 18F-FDG PET are not specific for malignancy because 18F-FDG is also accumulated in inflammatory lesions. It is known that the most important pathway for 18F-FDG to enter the cell body is mediated by the facilitative glucose transporter-1 (GLUT-1) through GLUT-3. We herein present a case of xanthogranulomatous cholecystitis (XGC) with a positive result on 18F-FDG PET. In this case, GLUT-1 and GLUT-3 were both positively expressed in inflammatory cells at the gallbladder wall of XGC and this is the first report to reveal GLUT expression in XGC. This report reveals that surgeons should carefully consider the appropriate treatment of gallbladder tumor, even with a positive result on 18F-FDG PET.

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