8OJP

Human galectin 1 in complex with inhibitor

Summary for 8OJP

• Entry DOI: 10.2210/pdb8ojp/pdb
• Descriptor: Galectin-1, (2~{R},3~{R},4~{S},5~{R},6~{R})-2-[3,5-bis(chloranyl)-4-fluoranyl-phenyl]sulfanyl-6-(hydroxymethyl)-4-[4-(1,3-thiazol-2-yl)-1,2,3-triazol-1-yl]oxane-3,5-diol, GLYCEROL, ... (4 entities in total)
• Functional Keywords: galectin, ligand, complex, sugar binding, sugar binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 30996.87

Authors

Hakansson, M.,Diehl, C.,Nilsson, U.J.,Zetterberg, F.R.,Peterson, K. (deposition date: 2023-03-24, release date: 2024-06-12, Last modification date: 2024-10-23)

Primary citation

Zetterberg, F.R.,Diehl, C.,Hakansson, M.,Kahl-Knutson, B.,Leffler, H.,Nilsson, U.J.,Peterson, K.,Roper, J.A.,Slack, R.J.
Discovery of Selective and Orally Available Galectin-1 Inhibitors.
J.Med.Chem., 66:16980-16990, 2023

PubMed Abstract: A new series of orally available α-d-galactopyranosides with high affinity and specificity toward galectin-1 have been discovered. High affinity and specificity were achieved by changing six-membered aryl-triazolyl substituents in a series of recently published galectin-3-selective α-d-thiogalactosides (e.g., GB1107 galectin-1/3 3.7/0.037 μM) for five-membered heterocycles such as thiazoles. The in vitro pharmacokinetic properties were optimized, resulting in several galectin-1 inhibitors with favorable properties. One compound, GB1490 ( galectin-1/3 0.4/2.7 μM), was selected for further characterization toward a panel of galectins showing a selectivity of 6- to 320-fold dependent on galectin. The X-ray structure of GB1490 bound to galectin-1 reveals the compound bound in a single conformation in the carbohydrate binding site. GB1490 was shown to reverse galectin-1-induced apoptosis of Jurkat cells at low μM concentrations. No cell cytotoxicity was observed for GB1490 up to 90 μM in the A549 cells. In pharmacokinetic studies in mice, GB1490 showed high oral bioavailability (% > 99%).

PubMed: 38059452
DOI: 10.1021/acs.jmedchem.3c01787

Experimental method

X-RAY DIFFRACTION (1.71 Å)