作者: Leffler, Hakon ; Zarrizi, Reihaneh ; Roper, James A ; Khabut, Areej ; Slack, Robert J ; Peterson, Kristoffer ; Nilsson, Ulf J ; Diehl, Carl ; Andréasson Dahlgren, Kajsa ; Pedersen, Anders ; Zetterberg, Fredrik R ; Håkansson, Maria ; Holyer, Ian ; Kahl-Knutson, Barbro ; MacKinnon, Alison C

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 (K_d galectin-1/3 0.057/6.0 μM). In vitro GB1908 inhibited galectin-1-induced apoptosis in Jurkat cells (IC₅₀ = 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.

2023-12-28·Journal of Medicinal Chemistry1区 · 医学

Discovery of Selective and Orally Available Galectin-1 Inhibitors

1区 · 医学

Article

作者: Diehl, Carl ; Peterson, Kristoffer ; Slack, Robert J. ; Leffler, Hakon ; Kahl-Knutson, Barbro ; Zetterberg, Fredrik R. ; Roper, James A. ; Nilsson, Ulf J. ; Håkansson, Maria

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 K_d 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 (K_d 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 (F% > 99%).

100 项与 GB-1490 相关的药物交易

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