ArticleThe Journal of pharmacology and experimental therapeutics2013
Structure-based optimization of angiostatic agent 6DBF7, an allosteric antagonist of galectin-1.
Article in The Journal of pharmacology and experimental therapeutics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 42 citations in OpenAlex.
- Network-based allosteric analysis of galectin-7: Key residues dictate functional communication and stability.Protein science : a publication of the Protein Society · 2026Article
- Glycosylation in the tumor immune response: the bitter side of sweetness.Acta biochimica et biophysica Sinica · 2024Review
- Regulation of Nrf2/Keap1 signaling pathway in cancer drug resistance by galectin-1: cellular and molecular implications.Cancer drug resistance (Alhambra, Calif.) · 2024Review
- Glycomimetics for the inhibition and modulation of lectins.Chemical Society reviews · 2023Review
- Targeting galectin-driven regulatory circuits in cancer and fibrosis.Nature reviews. Drug discovery · 2023Review
- Galectins and galectin-mediated autophagy regulation: new insights into targeted cancer therapy.Biomarker research · 2023Review
- Galectin functions in cancer-associated inflammation and thrombosis.Frontiers in cardiovascular medicine · 2023Review
- MG-International journal of molecular sciences · 2022Article
- Inhibition of galectins in cancer: Biological challenges for their clinical application.Frontiers in immunology · 2022Review
- Review
- Binding of a SolubleBiochemistry · 2020Article
- Galectins and Ovarian Cancer.Cancers · 2020Review
- Targeting Galectins With Glycomimetics.Frontiers in chemistry · 2020Review
- Increased plasma levels of galectin-1 in pancreatic cancer: potential use as biomarker.Oncotarget · 2018Article
- Galectins as Molecular Targets for Therapeutic Intervention.International journal of molecular sciences · 2018Review
- Galectin Targeted Therapy in Oncology: Current Knowledge and Perspectives.International journal of molecular sciences · 2018Review
- Rapalogs can promote cancer cell stemness in vitro in a Galectin-1 and H-ras-dependent manner.Oncotarget · 2017Article
- Triple-negative breast cancer targeting and killing by EpCAM-directed, plasmonically active nanodrug systems.NPJ precision oncology · 2017Article
- Low or No Inhibitory Potency of the Canonical Galectin Carbohydrate-binding Site by Pectins and Galactomannans.The Journal of biological chemistry · 2016Article
- Nonclassically Secreted Regulators of Angiogenesis.Angiology: open access · 2013Article
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7 authors at 1 institution in 1 country.
Funding
Abstract
Galectin-1 (gal-1), which binds β-galactoside groups on various cell surface receptors, is crucial to cell adhesion and migration, and is found to be elevated in several cancers. Previously, we reported on 6DBF7, a dibenzofuran (DBF)-based peptidomimetic of the gal-1 antagonist anginex. In the present study, we used a structure-based approach to optimize 6DBF7. Initial NMR studies showed that 6DBF7 binds to gal-1 on one side of the β-sandwich away from the lectin's carbohydrate binding site. Although an alanine scan of 6DBF7 showed that the two cationic groups (lysines) in the partial peptide are crucial to its angiostatic activity, it is the hydrophobic face of the amphipath that appears to interact directly with the surface of gal-1. Based on this structural information, we designed and tested additional DBF analogs. In particular, substitution of the C-terminal Asp for alanine and branched alkyl side chains (Val, Leu, Ile) for linear ones (Nle, Nva) rendered the greatest improvements in activity. Flow cytometry with gal-1(-/-) splenocytes showed that 6DBF7 and two of its more potent analogs (DB16 and DB21) can fully inhibit fluorescein isothiocyanate-gal-1 binding. Moreover, heteronuclear single-quantum coherence NMR titrations showed that the presence of DB16 decreases gal-1 affinity for lactose, indicating that the peptidomimetic targets gal-1 as a noncompetitive, allosteric inhibitor of glycan binding. Using tumor mouse models (B16F10 melanoma, LS174 lung, and MA148 ovarian), we found that DB21 inhibits tumor angiogenesis and tumor growth significantly better than 6DBF7, DB16, or anginex. DB21 is currently being developed further and holds promise for the management of human cancer in the clinic.
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