From Inhibition to Degradation: Can Galectin-3 Be Drugged by Heterobifunctional Degraders?
- 1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva Cesta 7, 1000 Ljubljana, Slovenia
Abstract
Several nanomolar galectin-3 inhibitors have advanced to clinical evaluation, which suggests that galectin-3 is a druggable target. These small-molecule inhibitors act by binding to the target protein and rely on an occupancy-driven mode of action that may not fully address intracellular functions of galectin-3. Proteolysis-targeting chimaeras (PROTACs) represent an alternative therapeutic modality, enabling intracellular target depletion with an event-driven mode of action. Galectin-3 is present both intracellularly and extracellularly; however, PROTACs can access only the intracellular pool, raising the question of whether selective intracellular degradation can provide sufficient therapeutic benefit. This perspective examines heterobifunctional galectin-3-targeting molecules composed of a glycomimetic ligand, an E3 ligase-recruiting ligand, and a linker. Their structures, degradation-related data, and mechanisms are critically assessed. Key challenges, including linker optimisation, ligand affinity, and intracellular target accessibility, are discussed. A very recent study demonstrated potent and selective galectin-3 degradation and expanded targeted protein degradation to structurally challenging lectins. Overall, galectin-3 represents a proof-of-principle that galectins undergoing intracellular–extracellular trafficking may potentially be degraded by PROTACs.
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BibTeX
@article{puric2026from,
title = {{From Inhibition to Degradation: Can Galectin-3 Be Drugged by Heterobifunctional Degraders?}},
author = {Edvin Purić},
journal = {Molecules},
year = {2026},
month = oct,
doi = {10.3390/molecules31213853},
url = {https://www.mdpi.com/1420-3049/31/21/3853},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - From Inhibition to Degradation: Can Galectin-3 Be Drugged by Heterobifunctional Degraders?
AU - Edvin Purić
PY - 2026
DA - 2026/10/26
JO - Molecules
DO - 10.3390/molecules31213853
UR - https://www.mdpi.com/1420-3049/31/21/3853
AB - Several nanomolar galectin-3 inhibitors have advanced to clinical evaluation, which suggests that galectin-3 is a druggable target. These small-molecule inhibitors act by binding to the target protein and rely on an occupancy-driven mode of action that may not fully address intracellular functions of galectin-3. Proteolysis-targeting chimaeras (PROTACs) represent an alternative therapeutic modality, enabling intracellular target depletion with an event-driven mode of action. Galectin-3 is present both intracellularly and extracellularly; however, PROTACs can access only the intracellular pool, raising the question of whether selective intracellular degradation can provide sufficient therapeutic benefit. This perspective examines heterobifunctional galectin-3-targeting molecules composed of a glycomimetic ligand, an E3 ligase-recruiting ligand, and a linker. Their structures, degradation-related data, and mechanisms are critically assessed. Key challenges, including linker optimisation, ligand affinity, and intracellular target accessibility, are discussed. A very recent study demonstrated potent and selective galectin-3 degradation and expanded targeted protein degradation to structurally challenging lectins. Overall, galectin-3 represents a proof-of-principle that galectins undergoing intracellular–extracellular trafficking may potentially be degraded by PROTACs.
SN - 1420-3049
ER -