Discovery of the Selective and Orally Available Galectin-1 Inhibitor GB1908 as a Potential Treatment for Lung Cancer

  • J Med Chem. 2024 Jun 13;67(11):9374-9388. doi: 10.1021/acs.jmedchem.4c00485.
Fredrik R Zetterberg  1 ,  Kristoffer Peterson  1 ,  Ulf J Nilsson  1  2 ,  Kajsa Andréasson Dahlgren  3 ,  Carl Diehl  4 ,  Ian Holyer  5 ,  Maria Håkansson  4 ,  Areej Khabut  3 ,  Barbro Kahl-Knutson  6 ,  Hakon Leffler  6 ,  Alison C MacKinnon  5 ,  James A Roper  7 ,  Robert J Slack  7 ,  Reihaneh Zarrizi  3 ,  Anders Pedersen  8
Affiliations
  • 1. Galecto Biotech AB, Sahlgrenska Science Park, Medicinaregatan 8 A, SE-413 46 Gothenburg,Sweden.
  • 2. Department of Chemistry, Lund University, Box 124, SE-221 00 Lund, Sweden.
  • 3. Red Glead Discovery AB, Medicon Village, SE-223 63 Lund, Sweden.
  • 4. SARomics Biostructures AB, Medicon Village, SE-223 63 Lund, Sweden.
  • 5. Nine Edinburgh Bioquarter, Galecto Biotech ApS, 9 Little France Road, Edinburgh EH16 4UX, U.K.
  • 6. Department of Laboratory Medicine, Lund University, Box 124, SE-221 00 Lund, Sweden.
  • 7. Stevenage Bioscience Catalyst, Galecto Biotech ApS, Stevenage, Hertfordshire SG1 2FX, U.K.
  • 8. Galecto Biotech AB, Cobis Science Park, Ole Maaloes Vej 3, DK-2200 Copenhagen, Denmark.
PMID: 38804039 DOI: 10.1021/acs.jmedchem.4c00485
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 (Kd 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 Kd for 24 h. GB1908 dosed with this regimen reduced the growth of primary lung tumor LL/2 in a syngeneic mouse model.

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