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J Biol Chem. 2015 Jun 5;290(23):14441-53. doi: 10.1074/jbc.M114.628826. Epub 2015 Apr 6.

In Silico Modeling-based Identification of Glucose Transporter 4 (GLUT4)-selective Inhibitors for Cancer Therapy.

Author information

1
From the Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois 60208.
2
the Department of Hematology and Medical Oncology, School of Medicine, Emory University, Atlanta, Georgia 30322.
3
the Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110.
4
the City of Hope, Duarte, California 91010, and.
5
the Department of Hematology and Medical Oncology, School of Medicine, Emory University, Atlanta, Georgia 30322 mala.shan@emory.edu.

Abstract

Tumor cells rely on elevated glucose consumption and metabolism for survival and proliferation. Glucose transporters mediating glucose entry are key proximal rate-limiting checkpoints. Unlike GLUT1 that is highly expressed in cancer and more ubiquitously expressed in normal tissues, GLUT4 exhibits more limited normal expression profiles. We have previously determined that insulin-responsive GLUT4 is constitutively localized on the plasma membrane of myeloma cells. Consequently, suppression of GLUT4 or inhibition of glucose transport with the HIV protease inhibitor ritonavir elicited growth arrest and/or apoptosis in multiple myeloma. GLUT4 inhibition also caused sensitization to metformin in multiple myeloma and chronic lymphocytic leukemia and a number of solid tumors suggesting the broader therapeutic utility of targeting GLUT4. This study sought to identify selective inhibitors of GLUT4 to develop a more potent cancer chemotherapeutic with fewer potential off-target effects. Recently, the crystal structure of GLUT1 in an inward open conformation was reported. Although this is an important achievement, a full understanding of the structural biology of facilitative glucose transport remains elusive. To date, there is no three-dimensional structure for GLUT4. We have generated a homology model for GLUT4 that we utilized to screen for drug-like compounds from a library of 18 million compounds. Despite 68% homology between GLUT1 and GLUT4, our virtual screen identified two potent compounds that were shown to target GLUT4 preferentially over GLUT1 and block glucose transport. Our results strongly bolster the utility of developing GLUT4-selective inhibitors as anti-cancer therapeutics.

KEYWORDS:

Warburg effect; cancer; glucose transport; glucose transporter type 4 (GLUT4); multiple myeloma

PMID:
25847249
PMCID:
PMC4505511
DOI:
10.1074/jbc.M114.628826
[Indexed for MEDLINE]
Free PMC Article

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