8r74 | pdb_00008r74
Galectin-1 in complex with thiogalactoside derivative
Structural highlights
FunctionLEG1_HUMAN May regulate apoptosis, cell proliferation and cell differentiation. Binds beta-galactoside and a wide array of complex carbohydrates. Inhibits CD45 protein phosphatase activity and therefore the dephosphorylation of Lyn kinase.[1] [2] Publication Abstract from PubMedWe have previously described a new series of selective and orally available galectin-1 inhibitors resulting in the thiazole-containing glycomimetic GB1490. Here, we show that the introduction of polar substituents to the thiazole ring results in galectin-1-specific compounds with low nM affinities. X-ray structural analysis of a new ligand-galectin-1 complex shows changes in the binding mode and ligand-protein hydrogen bond interactions compared to the GB1490-galectin-1 complex. These new high affinity ligands were further optimized with respect to affinity and ADME properties resulting in the galectin-1-selective GB1908 (K(d) galectin-1/3 0.057/6.0 muM). In vitro GB1908 inhibited galectin-1-induced apoptosis in Jurkat cells (IC(50) = 850 nM). Pharmacokinetic experiments in mice revealed that a dose of 30 mg/kg b.i.d. results in free levels of GB1908 in plasma over galectin-1 K(d) for 24 h. GB1908 dosed with this regimen reduced the growth of primary lung tumor LL/2 in a syngeneic mouse model. Discovery of the Selective and Orally Available Galectin-1 Inhibitor GB1908 as a Potential Treatment for Lung Cancer.,Zetterberg FR, Peterson K, Nilsson UJ, Andreasson Dahlgren K, Diehl C, Holyer I, Hakansson M, Khabut A, Kahl-Knutson B, Leffler H, MacKinnon AC, Roper JA, Slack RJ, Zarrizi R, Pedersen A J Med Chem. 2024 May 28. doi: 10.1021/acs.jmedchem.4c00485. PMID:38804039[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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