8R74

Galectin-1 in complex with thiogalactoside derivative

Summary for 8R74

• Entry DOI: 10.2210/pdb8r74/pdb
• Descriptor: Galectin-1, (2~{R},3~{R},4~{S},5~{R},6~{R})-2-(3,4-dichlorophenyl)sulfanyl-6-(hydroxymethyl)-4-[4-(2-oxidanyl-1,3-thiazol-4-yl)-1,2,3-triazol-1-yl]oxane-3,5-diol (3 entities in total)
• Functional Keywords: galectin, ligand, thiogalactoside derivative, sugar binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 30444.09

Authors

Hakansson, M.,Diehl, C.,Peterson, K.,Zetterberg, F.,Nilsson, U. (deposition date: 2023-11-23, release date: 2024-06-05, Last modification date: 2024-06-19)

Primary citation

Zetterberg, F.R.,Peterson, K.,Nilsson, U.J.,Andreasson Dahlgren, K.,Diehl, C.,Holyer, I.,Hakansson, M.,Khabut, A.,Kahl-Knutson, B.,Leffler, H.,MacKinnon, A.C.,Roper, J.A.,Slack, R.J.,Zarrizi, R.,Pedersen, A.
Discovery of the Selective and Orally Available Galectin-1 Inhibitor GB1908 as a Potential Treatment for Lung Cancer.
J.Med.Chem., 67:9374-9388, 2024

PubMed Abstract: We 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 ( galectin-1/3 0.057/6.0 μM). In vitro GB1908 inhibited galectin-1-induced apoptosis in Jurkat cells (IC = 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 for 24 h. GB1908 dosed with this regimen reduced the growth of primary lung tumor LL/2 in a syngeneic mouse model.

PubMed: 38804039
DOI: 10.1021/acs.jmedchem.4c00485

Experimental method

X-RAY DIFFRACTION (1.54 Å)