9s62 | pdb_00009s62
Galectin-3 in complex with N-[4-O-(beta-d-Galactopyranosyl)-beta-d-glucopyranosyl]-N-(3-carboxyphenyl)acetamide
Structural highlights
FunctionLEG3_HUMAN Galactose-specific lectin which binds IgE. May mediate with the alpha-3, beta-1 integrin the stimulation by CSPG4 of endothelial cells migration. Together with DMBT1, required for terminal differentiation of columnar epithelial cells during early embryogenesis (By similarity). In the nucleus: acts as a pre-mRNA splicing factor. Involved in acute inflammatory responses including neutrophil activation and adhesion, chemoattraction of monocytes macrophages, opsonization of apoptotic neutrophils, and activation of mast cells.[1] [2] [3] Publication Abstract from PubMedGalectin-3 (Gal-3) is a galactose-binding lectin involved in pathologies such as inflammation, fibrosis, heart disease, and tumor progression. Here, we report N-aryl-N-(thio)lactosylamides as a novel class of Gal-3 inhibitors. A structure-activity study identified 6-carboxyindol-4-yl amide as a key pharmacophoric motif within this series. The most potent inhibitor based on this motif, compound 11, binds to Gal-3 with excellent affinity (K(d) = 5.7 nM) and selectivity (390-fold over Gal-1). Further in vitro characterization of this compound demonstrated high metabolic stability and no cytotoxicity (CC(50) > 300 muM). Compound 11 effectively engages Gal-3 with greater activity in macrophage-like than monocyte-like THP1 cells, without affecting inflammation via LPS-induced release of TNFalpha. In TGFbeta-stimulated LX2 hepatic stellate cells, it downregulates profibrotic signaling as assessed by the reduced expression of ACTA2, COL1A2, and FN1. These findings implicate compound 11 as a promising candidate for further preclinical development in the context of fibrotic disease. N-Aryl-N-Lactosylamides as Potent and Highly Selective Inhibitors of Galectin-3 with Antifibrotic Activity.,Zyka J, Kozak J, Vanekova L, Pimkova Polidarova M, Prouza V, Habanova N, Strmen T, Zavrel M, Pachl P, Choutka J, Grantz Saskova K, Brazdova A, Parkan K, Pohl R J Med Chem. 2025 Nov 11. doi: 10.1021/acs.jmedchem.5c02604. PMID:41217252[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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