N-Aryl- N-Lactosylamides as Potent and Highly Selective Inhibitors of Galectin-3 with Antifibrotic Activity

  • J Med Chem. 2025 Nov 27;68(22):24624-24648. doi: 10.1021/acs.jmedchem.5c02604.
Jakub Zýka  1  2 ,  Jaroslav Kozák  1 ,  Lenka Vanekova  3 ,  Marketa Pimkova Polidarova  3 ,  Vít Prouza  1  2 ,  Nina Habanová  1 ,  Timotej Strmeň  1  4 ,  Martin Zavřel  1 ,  Petr Pachl  1 ,  Jan Choutka  1 ,  Klara Grantz Saskova  3 ,  Andrea Brazdova  3 ,  Kamil Parkan  1  2 ,  Radek Pohl  1
Affiliations
  • 1. Gilead Sciences & IOCB Research Centre, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 2, 166 10 Prague, Czech Republic.
  • 2. Department of Chemistry of Natural Compounds, University of Chemistry and Technology Prague, Technická 5, 166 28 Prague, Czech Republic.
  • 3. Department of Genetics and Microbiology, Faculty of Science, BIOCEV, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic.
  • 4. Department of Public Health and Clinical Medicine, Umeå University, 901 87 Umeå, Sweden.
PMID: 41217252 DOI: 10.1021/acs.jmedchem.5c02604
Abstract

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 (Kd = 5.7 nM) and selectivity (390-fold over Gal-1). Further in vitro characterization of this compound demonstrated high metabolic stability and no cytotoxicity (CC50 > 300 μM). 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 TNFα. In TGFβ-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.

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