Identification and Optimization of the First Highly Selective GLUT1 Inhibitor BAY‐876

Siebeneicher, Hölger; Cleve, Arwed; Rehwinkel, Hartmut; Neuhaus, Roland; Heisler, Iring; Müller, Thomas; Bauser, Marcus; Buchmann, Bernd

doi:10.1002/cmdc.201600276

Cited by 215 publications

(175 citation statements)

References 48 publications

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“…Antisense RNA targeting GLUT5 has proved effective against two breast cancer cells lines expressing this transporter [53]. Small molecule inhibitors specific for GLUT1, including WZB117 which we have utilized in our studies, have been identified [54], as have inhibitors for other transporters such as GLUT5 [55]. These molecules offer the opportunity to selectively target specific transporters as part of single or combination therapies.…”

Section: Discussionmentioning

confidence: 99%

The glucose transporter GLUT1 is required for ErbB2-induced mammary tumorigenesis

et al. 2016

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BackgroundAltered tumor cell metabolism is an emerging hallmark of cancer; however, the precise role for glucose in tumor initiation is not known. GLUT1 (SLC2A1) is expressed in breast cancer cells and is likely responsible for avid glucose uptake observed in established tumors. We have shown that GLUT1 was necessary for xenograft tumor formation from primary mammary cells transformed with the polyomavirus middle-T antigen but that it was not necessary for growth after tumors had formed in vivo, suggesting a differential requirement for glucose depending on the stage of tumorigenesis.MethodsTo determine whether GLUT1 is required early during mammary tumorigenesis, we crossed MMTV-NIC mice, which express activated HER2/NEU/ERBB2 and Cre recombinase, to Slc2a1 Flox/Flox (GLUT1Flox/Flox) mice to generate NIC-GLUT1+/+, NIC-GLUT1Flox/+, and NIC-GLUT1Flox/Flox mice. In addition, we evaluated effects of glucose restriction or GLUT1 inhibition on transformation in MCF10A-ERBB2 breast epithelial cells in three-dimensional culture. Finally, we utilized global gene expression profiling data of primary human breast tumors to determine the relationship between SLC2A1 and stage of tumorigenesis.ResultsAll of the NIC-GLUT1+/+ mice developed tumors in less than 200 days. In contrast, only 1 NIC-GLUT1Flox/Flox mouse and 1 NIC-GLUT1Flox/+ mouse developed mammary tumors, even after 18 months. Mammary gland development was not disrupted in NIC mice lacking GLUT1; however, epithelial content of mature glands was reduced compared to NIC-GLUT1Flox/+ mice. In MCF10A-ERBB2 cells, glucose restriction or GLUT1 inhibition blocked transformation induced by activated ERBB2 through reduced cell proliferation. In human breast cancers, SLC2A1 was higher in ductal carcinoma in situ compared to the normal breast, but lower in invasive versus in situ lesions, suggesting the requirement for GLUT1 decreases as tumors progress.ConclusionsThis study demonstrates a strict requirement for GLUT1 in the early stages of mammary tumorigenesis in vitro and in vivo. While metabolic adaptation has emerged as a hallmark of cancer, our data indicate that early tumor cells rely heavily on glucose and highlight the potential for glucose restriction as a breast cancer preventive strategy.

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Section: Discussionmentioning

confidence: 99%

The glucose transporter GLUT1 is required for ErbB2-induced mammary tumorigenesis

et al. 2016

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“…BAY‐876 (IC 50 =2 n m , Figure , Table ) possesses a clear preference for GLUT‐1 over GLUT‐2, ‐3, and ‐4. It competitively inhibits GLUT‐1 (Table ) and shows good in vitro and in vivo properties . However, BAY‐876 did not inhibit the growth of the triple‐negative breast cancer cell lines BT549, MDA‐MB‐436, and HCC70 at 3 μ m as determined by live‐cell imaging (Table ) .…”

Section: Discovery Of the Most Potent Glut Inhibitorsmentioning

confidence: 99%

“…GLUTs exhibit a tissue‐specific distribution and selective expression in cancer . GLUT‐1 is expressed at high levels in most cancers, and GLUT‐3 is predominantly found in the brain, arguing for the development of GLUT‐1‐selective compounds . However, GLUT‐3 is also overexpressed in numerous additional cancer types (beyond glioblastoma that originates from nervous tissue) such as breast and endometrial cancer, head and neck tumors, colon cancer, pancreatic cancer, non‐small cell lung cancer and thyroid carcinomas .…”

Section: Glut Isoform Selectivity Profiles To Target Cancermentioning

confidence: 99%

Small‐Molecule Inhibition of Glucose Transporters GLUT‐1–4

Reckzeh

Waldmann

2019

ChemBioChem

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Glucose addiction is observed in cancer and other diseases that are associated with hyperproliferation. The development of compounds that restrict glucose supply and decrease glycolysis has great potential for the development of new therapeutic approaches. Addressing facilitative glucose transporters (GLUTs), which are often upregulated in glucose‐dependent cells, is therefore of particular interest. This article reviews a selection of potent, isoform‐selective GLUT inhibitors and their biological characterization. Potential therapeutic applications of GLUT inhibitors in oncology and other diseases that are linked to glucose addiction are discussed.

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“…Extensive efforts have been made to discover new inhibitors of GLUTs, particularly GLUT1, as leads for developing novel anticancer drugs . Although a number of GLUT inhibitors have been reported, including BAY‐876, a potent and isoform‐specific GLUT1 inhibitor, none has entered the clinic to date.…”

Section: Figurementioning

confidence: 99%

Discovery of a Potent GLUT Inhibitor from a Library of Rapafucins by Using 3D Microarrays

et al. 2019

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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 IC50 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.

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Identification and Optimization of the First Highly Selective GLUT1 Inhibitor BAY‐876

Cited by 215 publications

References 48 publications

The glucose transporter GLUT1 is required for ErbB2-induced mammary tumorigenesis

The glucose transporter GLUT1 is required for ErbB2-induced mammary tumorigenesis

Small‐Molecule Inhibition of Glucose Transporters GLUT‐1–4

Discovery of a Potent GLUT Inhibitor from a Library of Rapafucins by Using 3D Microarrays

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