Title

Rational Design and Synthesis of Methyl-β-d-galactomalonyl Phenyl Esters as Potent Galectin-8N Antagonists

RIS ID

146239

Publication Details

Patel, B., Kishor, C., Houston, T., Shatz-Azoulay, H., Zick, Y., Vinik, Y. & Blanchard, H. (2020). Rational Design and Synthesis of Methyl-β-d-galactomalonyl Phenyl Esters as Potent Galectin-8N Antagonists. Journal of Medicinal Chemistry, 63 (20), 11573-11584.

Abstract

Galectin-8 is a β-galactoside-recognizing protein having an important role in the regulation of bone remodeling and cancer progression and metastasis. Methyl β-d-galactopyranoside malonyl aromatic esters have been designed to target and engage with particular amino acid residues of the galectin-8N extended carbohydrate-binding site. The chemically synthesized compounds had in vitro binding affinity toward galectin-8N in the range of 5-33 μM, as evaluated by isothermal titration calorimetry. This affinity directly correlated with the compounds' ability to inhibit galectin-8-induced expression of chemokines and proinflammatory cytokines in the SUM159 breast cancer cell line. X-ray crystallographic structure determination revealed that these monosaccharide-based compounds bind galectin-8N by engaging its unique arginine (Arg59) and simultaneously cross-linking to another arginine (Arg45) located across the carbohydrate-binding site. This structure-based drug design approach has led to the discovery of novel monosaccharide galactose-based antagonists, with the strongest-binding compound (Kd 5.72 μM) holding 7-fold tighter than the disaccharide lactose.

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Link to publisher version (DOI)

http://dx.doi.org/10.1021/acs.jmedchem.0c00602