1. Academic Validation
  2. Discovery of Selective and Orally Available Galectin-1 Inhibitors

Discovery of Selective and Orally Available Galectin-1 Inhibitors

  • J Med Chem. 2023 Dec 7. doi: 10.1021/acs.jmedchem.3c01787.
Fredrik R Zetterberg 1 Carl Diehl 2 Maria Håkansson 2 Barbro Kahl-Knutson 3 Hakon Leffler 3 Ulf J Nilsson 1 4 Kristoffer Peterson 1 James A Roper 5 Robert J Slack 5
Affiliations

Affiliations

  • 1 Galecto Biotech AB, Sahlgrenska Science Park, Medicinaregatan 8 A, SE-413 46 Gothenburg, Sweden.
  • 2 SARomics Biostructures AB, Medicon Village, SE-223 81 Lund, Sweden.
  • 3 Department of Laboratory Medicine, Lund University, Box 124, SE-221 00, Lund, Sweden.
  • 4 Department of Chemistry, Lund University, Box 124, SE-221 00 Lund, Sweden.
  • 5 Stevenage Bioscience Catalyst, Galecto Biotech ApS, Stevenage, Hertfordshire SG1 2FX U.K.
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 Kd 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 (Kd 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%).

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