An Orally Available Halothiazole Glycomimetic as a Cancer-Targeting Dual Galectin-1 and Galectin-3 Inhibitor

  • J Med Chem. 2026 May 14;69(9):10494-10514. doi: 10.1021/acs.jmedchem.5c03703.
Fredrik R Zetterberg  1 ,  Kristoffer Peterson  1 ,  Ulf J Nilsson  1  2 ,  Carl Diehl  3 ,  Maria Håkansson  3 ,  Barbro Kahl-Knutson  4 ,  Alison C MacKinnon  5 ,  Hanna Klein  6 ,  Hakon Leffler  4 ,  James A Roper  7 ,  Robert J Slack  7 ,  Henrik von Wachenfeldt  6 ,  Anders Pedersen  8
Affiliations
  • 1. Galecto Biotech AB, Sahlgrenska Science Park, Medicinaregatan 8 A, Gothenburg SE-413 46, Sweden.
  • 2. Department of Chemistry, Lund University, Box 124, Lund SE-221 00, Sweden.
  • 3. SARomics Biostructures AB, Medicon Village, Lund SE-223 81, Sweden.
  • 4. Department of Laboratory Medicine, Lund University, Box 124, Lund SE-221 00, Sweden.
  • 5. Galecto Biotech ApS, Nine Edinburgh Bioquarter, 9 Little France Road, Edinburgh EH16 4UX, U.K.
  • 6. RG Discovery AB, Medicon Village, Lund SE-223 63, Sweden.
  • 7. Galecto Biotech ApS, Stevenage Bioscience Catalyst, Stevenage, Hertfordshire SG1 2FX, U.K.
  • 8. Galecto Biotech AB, Cobis Science Park, Ole Maaloes Vej 3, Copenhagen DK-2200, Denmark.
PMID: 42052938 DOI: 10.1021/acs.jmedchem.5c03703
Abstract

Inhibition of several of the 10 hallmarks of Cancer (Hanahan and Weinberg) would result in a broader and more durable treatment compared to current single or combination drug treatments. Galectin-1 and Galectin-3 have been proposed to together be involved in all 10 hallmarks, suggesting that development of a combined Galectin-1/3 inhibitor would be beneficial. Specificity toward Galectin-1 or -3 can be modulated using different aryl moieties in 3-(aryl)triazolyl-galactopyranoside derivatives. By combining these findings, a new class of 3-(halothiazolyl)triazolyl derivatives with high affinity for both human Galectin-1 and -3 were discovered and optimized with respect to SAR and in vitro ADME parameters, resulting in GB1841 (Kd Galectin-1/-3 0.027/0.14 μM). Both selective and dual inhibition of Galectin-1 and Galectin-3 significantly reduces the growth of LL/2 lung Cancer cells in a syngeneic mouse model, supporting further development of GB1841 as a dual inhibitor of Galectin-1 and Galectin-3.

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