9s62

Publication Abstract from PubMed

Galectin-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.