期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 55, 期 11, 页码 5121-5129出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm300014q
关键词
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资金
- National Cancer Institute (NIH) [R01 CA096090]
- National Institutes of Health (NIH) [T32 CA009138]
- National Science Foundation [BIR-961477]
- University of Minnesota Medical School
- Minnesota Medical Foundation
- OncoEthix
- Foundation Nelia & Amadeo Barleta (FNAB)
- Association pour la Recherche & l'Enseignement en Cancerologie (AAREC)
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, N-15-H-1 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.
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