Ligand-based Design of GLUT Inhibitors As Potential Antitumor Agents

Overview

Journal Bioorg Med Chem

Specialties Biochemistry
Chemistry

Date 2020 Mar 2

PMID 32113844

Citations 4

Authors

Suliman Almahmoud

Wei Jin

Liying Geng

Jing Wang

Xiaofang Wang

Jonathan L Vennerstrom

Haizhen A Zhong

Affiliations

Soon will be listed here.

Abstract

Glucose transporters (GLUTs) regulate glucose uptake and are often overexpressed in several human tumors. To identify new chemotypes targeting GLUT1, we built a pharmacophore model and searched against a NCI compound database. Sixteen hit molecules with good docking scores were screened for GLUT1 inhibition and antiproliferative activities. From these, we identified that compounds 2, 5, 6 and 13 inhibited the cell viability in a dose-dependent manner and that the ICs of 2 and 6 are<10 µM concentration in the HCT116 colon cancer cell line. Lead compound 13 (NSC295720) was a GLUT1 inhibitor. Docking studies show that GLUT1 residues Phe291, Phe379, Glu380, Trp388, and Trp412 were important for inhibitor binding.

Citing Articles

New strategies to enhance the efficiency and precision of drug discovery.

An Q, Huang L, Wang C, Wang D, Tu Y Front Pharmacol. 2025; 16:1550158.

PMID: 40008135 PMC: 11850385. DOI: 10.3389/fphar.2025.1550158.

Enhanced Antitumor Efficacy and Reduced Toxicity in Colorectal Cancer Using a Novel Multifunctional Rg3- Targeting Nanosystem Encapsulated with Oxaliplatin and Calcium Peroxide.

Xie Y, Zhu M, Bao H, Chen K, Wang S, Dai J Int J Nanomedicine. 2025; 20:1021-1046.

PMID: 39877588 PMC: 11774109. DOI: 10.2147/IJN.S502076.

Ensemble-Based Virtual Screening Led to the Discovery of Novel Lead Molecules as Potential NMBAs.

Zhang Y, Ge G, Xu X, Wu J Molecules. 2024; 29(9).

PMID: 38731447 PMC: 11085220. DOI: 10.3390/molecules29091955.

Targeting Glucose Metabolism Enzymes in Cancer Treatment: Current and Emerging Strategies.

Zhang Y, Li Q, Huang Z, Li B, Nice E, Huang C Cancers (Basel). 2022; 14(19).

PMID: 36230492 PMC: 9559313. DOI: 10.3390/cancers14194568.

Identification of novel inhibitors of GLUT1 by virtual screening and cell-based assays.

Chen X, Zhao Y, Lyu S, Gao G, Gao Y, Qi Y Invest New Drugs. 2021; 39(5):1242-1255.

PMID: 33900490 DOI: 10.1007/s10637-021-01109-2.

References

Katagiri H, Asano T, Ishihara H, Lin J, Inukai K, Shanahan M . Role of tryptophan-388 of GLUT1 glucose transporter in glucose-transport activity and photoaffinity-labelling with forskolin. Biochem J. 1993; 291 ( Pt 3):861-7. PMC: 1132448. DOI: 10.1042/bj2910861. View

Rastogi S, Banerjee S, Chellappan S, Simon G . Glut-1 antibodies induce growth arrest and apoptosis in human cancer cell lines. Cancer Lett. 2007; 257(2):244-51. DOI: 10.1016/j.canlet.2007.07.021. View

Deng D, Xu C, Sun P, Wu J, Yan C, Hu M . Crystal structure of the human glucose transporter GLUT1. Nature. 2014; 510(7503):121-5. DOI: 10.1038/nature13306. View

Sasaki H, Shitara M, Yokota K, Hikosaka Y, Moriyama S, Yano M . Overexpression of GLUT1 correlates with Kras mutations in lung carcinomas. Mol Med Rep. 2011; 5(3):599-602. DOI: 10.3892/mmr.2011.736. View

Garcia J, Strube M, Leingang K, Keller K, Mueckler M . Amino acid substitutions at tryptophan 388 and tryptophan 412 of the HepG2 (Glut1) glucose transporter inhibit transport activity and targeting to the plasma membrane in Xenopus oocytes. J Biol Chem. 1992; 267(11):7770-6. View

Almahmoud S, Wang X, Vennerstrom J, Zhong H . Conformational Studies of Glucose Transporter 1 (GLUT1) as an Anticancer Drug Target. Molecules. 2019; 24(11). PMC: 6600248. DOI: 10.3390/molecules24112159. View

Sheu J, Guan B, Tsai F, Hsiao E, Chen C, Seruca R . Mutant BRAF induces DNA strand breaks, activates DNA damage response pathway, and up-regulates glucose transporter-1 in nontransformed epithelial cells. Am J Pathol. 2012; 180(3):1179-1188. PMC: 4429179. DOI: 10.1016/j.ajpath.2011.11.026. View

Schwartzenberg-Bar-Yoseph F, Armoni M, Karnieli E . The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res. 2004; 64(7):2627-33. DOI: 10.1158/0008-5472.can-03-0846. View

Li N, Ragheb K, Lawler G, Sturgis J, Rajwa B, Melendez J . Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. J Biol Chem. 2002; 278(10):8516-25. DOI: 10.1074/jbc.M210432200. View

10.

Simpson I, Dwyer D, Malide D, Moley K, Travis A, Vannucci S . The facilitative glucose transporter GLUT3: 20 years of distinction. Am J Physiol Endocrinol Metab. 2008; 295(2):E242-53. PMC: 2519757. DOI: 10.1152/ajpendo.90388.2008. View

11.

Salas M, Obando P, Ojeda L, Ojeda P, Perez A, Vargas-Uribe M . Resolution of the direct interaction with and inhibition of the human GLUT1 hexose transporter by resveratrol from its effect on glucose accumulation. Am J Physiol Cell Physiol. 2013; 305(1):C90-9. DOI: 10.1152/ajpcell.00387.2012. View

12.

Patching S . Glucose Transporters at the Blood-Brain Barrier: Function, Regulation and Gateways for Drug Delivery. Mol Neurobiol. 2016; 54(2):1046-1077. DOI: 10.1007/s12035-015-9672-6. View

13.

Warburg O, Wind F, Negelein E . THE METABOLISM OF TUMORS IN THE BODY. J Gen Physiol. 2009; 8(6):519-30. PMC: 2140820. DOI: 10.1085/jgp.8.6.519. View

14.

Navale A, Paranjape A . Glucose transporters: physiological and pathological roles. Biophys Rev. 2017; 8(1):5-9. PMC: 5425736. DOI: 10.1007/s12551-015-0186-2. View

15.

Brown R, Wahl R . Overexpression of Glut-1 glucose transporter in human breast cancer. An immunohistochemical study. Cancer. 1993; 72(10):2979-85. DOI: 10.1002/1097-0142(19931115)72:10<2979::aid-cncr2820721020>3.0.co;2-x. View

16.

Gielisch I, Meierhofer D . Metabolome and proteome profiling of complex I deficiency induced by rotenone. J Proteome Res. 2014; 14(1):224-35. DOI: 10.1021/pr500894v. View

17.

Thorens B, Mueckler M . Glucose transporters in the 21st Century. Am J Physiol Endocrinol Metab. 2009; 298(2):E141-5. PMC: 2822486. DOI: 10.1152/ajpendo.00712.2009. View

18.

Chan D, Sutphin P, Nguyen P, Turcotte S, Lai E, Banh A . Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Sci Transl Med. 2011; 3(94):94ra70. PMC: 3683134. DOI: 10.1126/scitranslmed.3002394. View

19.

Barron C, Bilan P, Tsakiridis T, Tsiani E . Facilitative glucose transporters: Implications for cancer detection, prognosis and treatment. Metabolism. 2016; 65(2):124-39. DOI: 10.1016/j.metabol.2015.10.007. View

20.

LINDAHL P, Oberg K . The effect of rotenone on respiration and its point of attack. Exp Cell Res. 1961; 23:228-37. DOI: 10.1016/0014-4827(61)90033-7. View