| 1. |
- Aslanis, Vassilios, et al.
(author)
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Safety and pharmacokinetics of GB1211, an oral galectin-3 inhibitor : a single- and multiple-dose first-in-human study in healthy participants
- 2023
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In: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 91:3, s. 267-280
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Journal article (peer-reviewed)abstract
- PURPOSE: Galectin-3, a β-galactoside-binding lectin, plays a key role in several cellular pathways involved in chronic inflammation, heart disease and cancer. GB1211 is an orally bioavailable galectin-3 inhibitor, developed to be systemically active. We report safety and pharmacokinetics (PK) of GB1211 in healthy participants.METHODS: This phase 1, double-blind, placebo-controlled, first-in-human study (NCT03809052) included a single ascending-dose phase (with a food-effect cohort) where participants across seven sequential cohorts were randomized 3:1 to receive oral GB1211 (5, 20, 50, 100, 200 or 400 mg) or placebo. In the multiple ascending-dose phase, participants received 50 or 100 mg GB1211 or placebo twice daily for 10 days. All doses were administered in the fasted state except in the food-effect cohort where doses were given 30 min after a high-fat meal.RESULTS: All 78 participants received at least one GB1211 dose (n = 58) or placebo (n = 20) and completed the study. No safety concerns were identified. Following single and multiple oral doses under fasted conditions, maximum GB1211 plasma concentrations were reached at 1.75-4 h (median) post-dose; mean half-life was 11-16 h. There was a ~ twofold GB1211 accumulation in plasma with multiple dosing, with steady-state reached within 3 days; 30% of the administered dose was excreted in urine as unchanged drug. Absorption in the fed state was delayed by 2 h but systemic exposure was unaffected.CONCLUSION: GB1211 was well tolerated, rapidly absorbed, and displayed favorable PK, indicating a potential to treat multiple disease types. These findings support further clinical development of GB1211.CLINICAL TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov (identifier: NCT03809052).
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| 2. |
- Delaine, Tamara, et al.
(author)
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Galectin-3-Binding Glycomimetics that Strongly Reduce Bleomycin-Induced Lung Fibrosis and Modulate Intracellular Glycan Recognition
- 2016
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In: ChemBioChem. - : Wiley. - 1439-4227. ; 17:18, s. 1759-1770
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Journal article (peer-reviewed)abstract
- Discovery of glycan-competitive galectin-3-binding compounds that attenuate lung fibrosis in a murine model and that block intracellular galectin-3 accumulation at damaged vesicles, hence revealing galectin-3-glycan interactions involved in fibrosis progression and in intracellular galectin-3 activities, is reported. 3,3'-Bis-(4-aryltriazol-1-yl)thiodigalactosides were synthesized and evaluated as antagonists of galectin-1, -2, -3, and -4 N-terminal, -4 C-terminal, -7 and -8 N-terminal, -9 N-terminal, and -9 C-terminal domains. Compounds displaying low-nanomolar affinities for galectins-1 and -3 were identified in a competitive fluorescence anisotropy assay. X-ray structural analysis of selected compounds in complex with galectin-3, together with galectin-3 mutant binding experiments, revealed that both the aryltriazolyl moieties and fluoro substituents on the compounds are involved in key interactions responsible for exceptional affinities towards galectin-3. The most potent galectin-3 antagonist was demonstrated to act in an assay monitoring galectin-3 accumulation upon amitriptyline-induced vesicle damage, visualizing a biochemically/medically relevant intracellular lectin-carbohydrate binding event and that it can be blocked by a small molecule. The same antagonist administered intratracheally attenuated bleomycin-induced pulmonary fibrosis in a mouse model with a dose/response profile comparing favorably with that of oral administration of the marketed antifibrotic compound pirfenidone.
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| 3. |
- Hirani, Nikhil, et al.
(author)
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Target inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis
- 2021
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In: European Respiratory Journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 57:5
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Journal article (peer-reviewed)abstract
- Galectin (Gal)-3 is a profibrotic β-galactoside-binding lectin that plays a key role in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and IPF exacerbations. TD139 is a novel and potent small-molecule inhibitor of Gal-3. A randomised, double-blind, multicentre, placebo-controlled, phase 1/2a study was conducted to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled TD139 in 36 healthy subjects and 24 patients with IPF. Six dose cohorts of six healthy subjects were evaluated (4:2 TD139:placebo ratio) with single doses of TD139 (0.15–50 mg) and three dose cohorts of eight patients with IPF (5:3 TD139: placebo ratio) with once-daily doses of TD139 (0.3–10 mg) for 14 days. Inhaled TD139 was well tolerated with no significant treatment-related side-effects. TD139 was rapidly absorbed, with mean time taken to reach maximum plasma concentration (Cmax) values ranging from 0.6 to 3 h and a plasma half-life (T1/2) of 8 h. The concentration of TD139 in the lung was >567-fold higher than in the blood, with systemic exposure predicting exposure in the target compartment. Gal-3 expression on alveolar macrophages was reduced in the 3 and 10 mg dose groups compared with placebo, with a concentration-dependent inhibition demonstrated. Inhibition of Gal-3 expression in the lung was associated with reductions in plasma biomarkers centrally relevant to IPF pathobiology (platelet-derived growth factor-BB, plasminogen activator inhibitor-1, Gal-3, CCL18 and YKL-40). TD139 is safe and well tolerated in healthy subjects and IPF patients. It was shown to suppress Gal-3 expression on bronchoalveolar lavage macrophages and, in a concerted fashion, decrease plasma biomarkers associated with IPF progression.
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| 4. |
- Humphries, Duncan C., et al.
(author)
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Galectin-3 inhibitor GB0139 protects against acute lung injury by inhibiting neutrophil recruitment and activation
- 2022
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In: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 13
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Journal article (peer-reviewed)abstract
- Rationale: Galectin-3 (Gal-3) drives fibrosis during chronic lung injury, however, its role in acute lung injury (ALI) remains unknown. Effective pharmacological therapies available for ALI are limited; identifying novel concepts in treatment is essential. GB0139 is a Gal-3 inhibitor currently under clinical investigation for the treatment of idiopathic pulmonary fibrosis. We investigate the role of Gal-3 in ALI and evaluate whether its inhibition with GB0139 offers a protective role. The effect of GB0139 on ALI was explored in vivo and in vitro. Methods: The pharmacokinetic profile of intra-tracheal (i.t.) GB0139 was investigated in C57BL/6 mice to support the daily dosing regimen. GB0139 (1–30 µg) was then assessed following acute i.t. lipopolysaccharide (LPS) and bleomycin administration. Histology, broncho-alveolar lavage fluid (BALf) analysis, and flow cytometric analysis of lung digests and BALf were performed. The impact of GB0139 on cell activation and apoptosis was determined in vitro using neutrophils and THP-1, A549 and Jurkat E6 cell lines. Results: GB0139 decreased inflammation severity via a reduction in neutrophil and macrophage recruitment and neutrophil activation. GB0139 reduced LPS-mediated increases in interleukin (IL)-6, tumor necrosis factor alpha (TNFα) and macrophage inflammatory protein-1-alpha. In vitro, GB0139 inhibited Gal-3-induced neutrophil activation, monocyte IL-8 secretion, T cell apoptosis and the upregulation of pro-inflammatory genes encoding for IL-8, TNFα, IL-6 in alveolar epithelial cells in response to mechanical stretch. Conclusion: These data indicate that Gal-3 adopts a pro-inflammatory role following the early stages of lung injury and supports the development of GB0139, as a potential treatment approach in ALI.
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| 5. |
- Mackinnon, Alison, et al.
(author)
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Design, synthesis, And applications of galectin modulators in human health
- 2014
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In: Carbohydrates as Drugs. - Cham : Springer International Publishing. - 1862-247X .- 1862-2461. - 9783319086743 - 9783319345376 - 9783319086750 ; , s. 95-122
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Book chapter (peer-reviewed)abstract
- Over the last decade, the family of galectin proteins has been identified as key regulators of important biological processes. They bind β-D-galactopyranoside residues in glycoconjugates, and by presenting multiple binding sites, within one galectin or by forming dimers or multimers, they can cross-link glycoproteins and form galectin-glycoprotein lattices. Such lattices formed on the cell surface or in vesicles have been shown to control, for example, surface residence time and signaling by receptors. Hence, compounds modulating galectin binding to their glycoprotein ligands are of potential clinical interest. This chapter describes the design and development of disubstituted thiodigalactoside derivatives that form optimal interactions with the galectin-3 binding site resulting in double-digit nanomolar affinities. Studies are discussed in which such galectin-3-modulating compounds have been important in elucidating galectin-3 mechanisms, including galectin-3 trafficking, cancer, inflammation, fibrosis, and angiogenesis. Medically relevant models using the galectin-3 modulators in characterizing macrophage alternative activation and chronic inflammation, myofibroblast activation and fibrosis, and ocular angiogenesis are discussed in more detail. In summary, the high galectin-3 affinity and definitive effects in relevant models of the disubstituted thiodigalactosides identify them as promising as lead compounds for drug development, albeit leaving a challenge in terms of optimizing PK/ADME properties.
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| 6. |
- Rajput, Vishal K., et al.
(author)
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A Selective Galactose–Coumarin-Derived Galectin-3 Inhibitor Demonstrates Involvement of Galectin-3-glycan Interactions in a Pulmonary Fibrosis Model
- 2016
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 59:17, s. 8141-8147
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Journal article (peer-reviewed)abstract
- Synthesis of doubly 3-O-coumarylmethyl-substituted thiodigalactosides from bis-3-O-propargyl-thiodigalactoside resulted in highly selective and high affinity galectin-3 inhibitors. Mutant studies, structural analysis, and molecular modeling revealed that the coumaryl substituents stack onto arginine side chains. One inhibitor displayed efficacy in a murine model of bleomycin-induced lung fibrosis similar to that of a known nonselective galectin-1/galectin-3 inhibitor, which strongly suggests that blocking galectin-3 glycan recognition is an important antifibrotic drug target.
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| 7. |
- Stegmayr, John, et al.
(author)
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Extracellular and intracellular small-molecule galectin-3 inhibitors
- 2019
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
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Journal article (peer-reviewed)abstract
- Galectin-3 is a carbohydrate binding protein which has important roles in cancer and immunity. Potent galectin-3 inhibitors have been synthesized, for experimental purposes and potential clinical use. As galectin-3 is implicated in both intra- and extracellular activities, permeability of galectin-3 inhibitors is an important parameter determining biological effects. We compared the cellular uptake of galectin-3 inhibitors and their potency in the intracellular or extracellular space. The inhibitors differed in their polar surface area (PSA), but had similar affinities for galectin-3. Using a well-established permeability assay, we confirmed that the uptake was significantly higher for the inhibitor with the lowest PSA, as expected. To analyze intracellular activity of the inhibitors, we developed a novel assay based on galectin-3 accumulation around damaged intracellular vesicles. The results show striking differences between the inhibitors intracellular potency, correlating with their PSAs. To test extracellular activity of the inhibitors, we analyzed their potency to block binding of galectin-3 to cell surfaces. All inhibitors were equally able to block galectin-3 binding to cells and this was proportional to their affinity for galectin-3. These inhibitors may serve as useful tools in exploring biological roles of galectin-3 and may further our understanding of intracellular versus extracellular roles of galectin-3.
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| 8. |
- Vuong, Lynda, et al.
(author)
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An orally active galectin-3 antagonist inhibits lung adenocarcinoma growth and augments response to PD-L1 blockade
- 2019
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In: Cancer Research. - 0008-5472. ; 79:7, s. 1480-1492
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Journal article (peer-reviewed)abstract
- A combination therapy approach is required to improve tumor immune infiltration and patient response to immune checkpoint inhibitors that target negative regulatory receptors. Galectin-3 is a β-galactoside-binding lectin that is highly expressed within the tumor microenvironment of aggressive cancers and whose expression correlates with poor survival particularly in patients with non-small cell lung cancer (NSCLC). To examine the role of galectin-3 inhibition in NSCLC, we tested the effects of galectin-3 depletion using genetic and pharmacologic approaches on syngeneic mouse lung adenocarcinoma and human lung adenocarcinoma xenografts. Galectin-3-/- mice developed significantly smaller and fewer tumors and metastases than syngeneic C57/ Bl6 wild-type mice. Macrophage ablation retarded tumor growth, whereas reconstitution with galectin-3-positive bone marrow restored tumor growth in galectin-3-/- mice, indicating that macrophages were a major driver of the antitumor response. Oral administration of a novel small molecule galectin-3 inhibitor GB1107 reduced human and mouse lung adenocarcinoma growth and blocked metastasis in the syngeneic model. Treatment with GB1107 increased tumor M1 macrophage polarization and CD8 + T-cell infiltration. Moreover, GB1107 potentiated the effects of a PD-L1 immune checkpoint inhibitor to increase expression of cytotoxic (IFNγ, granzyme B, perforin-1, Fas ligand) and apoptotic (cleaved caspase-3) effector molecules. In summary, galectin-3 is an important regulator of lung adenocarcinoma progression. The novel galectin-3 inhibitor presented could provide an effective, nontoxic monotherapy or be used in combination with immune checkpoint inhibitors to boost immune infiltration and responses in lung adenocarcinoma and potentially other aggressive cancers. Significance: A novel and orally active galectin-3 antagonist inhibits lung adenocarcinoma growth and metastasis and augments response to PD-L1 blockade.
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| 9. |
- Zetterberg, Fredrik R., et al.
(author)
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Discovery and Optimization of the First Highly Effective and Orally Available Galectin-3 Inhibitors for Treatment of Fibrotic Disease
- 2022
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 65:19, s. 12626-12638
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Journal article (peer-reviewed)abstract
- Galectin-3 is a carbohydrate-binding protein central to regulating mechanisms of diseases such as fibrosis, cancer, metabolic, inflammatory, and heart disease. We recently found a high affinity (nM) thiodigalactoside GB0139 which currently is in clinical development (PhIIb) as an inhaled treatment of idiopathic pulmonary fibrosis. To enable treatment of systemically galectin-3 driven disease, we here present the first series of selective galectin-3 inhibitors combining high affinity (nM) with oral bioavailability. This was achieved by optimizing galectin-3 specificity and physical chemical parameters for a series of disubstituted monogalactosides. Further characterization showed that this class of compounds reduced profibrotic gene expression in liver myofibroblasts and displayed antifibrotic activity in CCl4-induced liver fibrosis and bleomycin-induced lung fibrosis mouse models. On the basis of the overall pharmacokinetic, pharmacodynamic, and safety profile, GB1211 was selected as the clinical candidate and is currently in phase IIa clinical trials as a potential therapy for liver cirrhosis and cancer.
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