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Human Galectin-3 CRD in complex with novel tetrahydropyran-based thiodisaccharide mimic inhibitorHuman Galectin-3 CRD in complex with novel tetrahydropyran-based thiodisaccharide mimic inhibitor
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 is a member of a family of beta-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 36, 40, and 45 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. Synthesis, Structure-Activity Relationships, and In Vivo Evaluation of Novel Tetrahydropyran-Based Thiodisaccharide Mimics as Galectin-3 Inhibitors.,Xu L, Hartz RA, Beno BR, Ghosh K, Shukla JK, Kumar A, Patel D, Kalidindi N, Lemos N, Gautam SS, Kumar A, Ellsworth BA, Shah D, Sale H, Cheng D, Regueiro-Ren A J Med Chem. 2021 May 27;64(10):6634-6655. doi: 10.1021/acs.jmedchem.0c02001. Epub, 2021 May 14. PMID:33988358[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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