7DF6

Mouse Galectin-3 CRD in complex with novel tetrahydropyran-based thiodisaccharide mimic inhibitor

Summary for 7DF6

• Entry DOI: 10.2210/pdb7df6/pdb
• Related: 7DF5
• Descriptor: Galectin-3, (2R,3R,4S,5R,6S)-2-(hydroxymethyl)-5-methoxy-6-[(3R,4R,5S)-4-oxidanyl-5-(4-pyrimidin-5-yl-1,2,3-triazol-1-yl)oxan-3-yl]sulfanyl-4-[4-[3,4,5-tris(fluoranyl)phenyl]-1,2,3-triazol-1-yl]oxan-3-ol (3 entities in total)
• Functional Keywords: galectin-3 carbohydrate recognition domain, inhibitor, complex, tetrahydropyran, thiodigalactoside, carbohydrate
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 2
• Total formula weight: 38551.70

Authors

Ghosh, K.,Kumar, A. (deposition date: 2020-11-06, release date: 2021-06-23, Last modification date: 2023-11-29)

Primary citation

Xu, L.,Hartz, R.A.,Beno, B.R.,Ghosh, K.,Shukla, J.K.,Kumar, A.,Patel, D.,Kalidindi, N.,Lemos, N.,Gautam, S.S.,Kumar, A.,Ellsworth, B.A.,Shah, D.,Sale, H.,Cheng, D.,Regueiro-Ren, A.
Synthesis, Structure-Activity Relationships, and In Vivo Evaluation of Novel Tetrahydropyran-Based Thiodisaccharide Mimics as Galectin-3 Inhibitors.
J.Med.Chem., 64:6634-6655, 2021

PubMed Abstract: Galectin-3 is a member of a family of β-galactoside-binding proteins. A substantial body of literature reports that galectin-3 plays important roles in cancer, inflammation, and fibrosis. Small-molecule galectin-3 inhibitors, which are generally lactose or galactose-based derivatives, have the potential to be valuable disease-modifying agents. In our efforts to identify novel galectin-3 disaccharide mimics to improve drug-like properties, we found that one of the monosaccharide subunits can be replaced with a suitably functionalized tetrahydropyran ring. Optimization of the structure-activity relationships around the tetrahydropyran-based scaffold led to the discovery of potent galectin-3 inhibitors. Compounds , , and were selected for further in vivo evaluation. The synthesis, structure-activity relationships, and in vivo evaluation of novel tetrahydropyran-based galectin-3 inhibitors are described.

PubMed: 33988358
DOI: 10.1021/acs.jmedchem.0c02001

Experimental method

X-RAY DIFFRACTION (1.8 Å)