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J Med Chem. 2012 Jun 14;55(11):5121-9. doi: 10.1021/jm300014q. Epub 2012 May 30.

Antitumor agent calixarene 0118 targets human galectin-1 as an allosteric inhibitor of carbohydrate binding.

Author information

1
Department of Biochemistry, Molecular Biology & Biophysics, University of Minnesota Health Sciences Center, 6-155 Jackson Hall, 321 Church Street, Minneapolis, Minnesota 55455, United States.

Abstract

Calix[4]arene compound 0118 is an angiostatic agent that inhibits tumor growth in mice. Although 0118 is a topomimetic of galectin-1-targeting angiostatic amphipathic peptide Anginex, we had yet to prove that 0118 targets galectin-1. Galectin-1 is involved in pathological disorders like tumor endothelial cell adhesion and migration and therefore presents a relevant target for therapeutic intervention against cancer. Here, (15)N-(1)H HSQC NMR spectroscopy demonstrates that 0118 indeed targets galectin-1 at a site away from the lectin's carbohydrate binding site and thereby attenuates lactose binding to the lectin. Flow cytometry and agglutination assays show that 0118 attenuates binding of galectin-1 to cell surface glycans, and the inhibition of cell proliferation by 0118 is found to be correlated with the cellular expression of the lectin. In general, our data indicate that 0118 targets galectin-1 as an allosteric inhibitor of glycan/carbohydrate binding. This work contributes to the clinical development of antitumor calixarene compound 0118.

PMID:
22575017
PMCID:
PMC4242090
DOI:
10.1021/jm300014q
[Indexed for MEDLINE]
Free PMC Article

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