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Background and Purpose: Galectin-3 (Gal-3) is a pro-fibrotic β-galactoside binding lectin highly expressed in fibrotic liver and implicated in hepatic fibrosis. GB1107 is a novel orally active Gal-3 small molecule inhibitor that has high affinity for Gal-3 >1000-fold selectively over other galectins. The aim of this study was to characterise GB1107 and galectin-3 in vitro and in vivo in the context of fibrosis signalling and liver disease., Experimental Approach: Liver fibrosis was induced by administration of CCl 4 twice weekly by intraperitoneal injection in mice for 8 weeks. GB1107 was orally administered once daily (10 mg/kg) for the last 4 weeks of CCl 4 treatment. Fibrosis was assessed by picrosirius red staining of FFPE sections. Liver enzymes, Gal-3 and downstream biomarkers were assessed in liver and plasma. Paired-end sequencing was performed on the Nextseq 2000 platform. Pathway enrichment analysis was performed to determine enrichment of differentially expressed genes (DEGs) within Reactome pathways and Gene Ontology (GO) terms., Key Results: GB1107 significantly reduced plasma transaminases and liver Gal-3 and reduced liver fibrosis. RNAseq analysis of whole liver showed that 1659 DEGs were identified with CCl 4 treatment compared to control. Pathways enriched in up-regulated genes in the CCl 4 group included those related to the extracellular matrix, collagen biosynthesis and assembly, cell cycle and the immune system. Comparing GB1107 treatment with CCl 4 control 1147 DEGs were identified. GB1107 effectively reversed the majority of the CCl 4 induced gene changes., Conclusions and Implications: GB1107 attenuated liver fibrosis and highlights Gal-3 as a therapeutic target for hepatic fibrosis., Competing Interests: Declaration of competing interest Conflict of interest disclosure: DH, JR, IH, JM, RJS, ACM, AP, FZ, HS: employees, personal fees – Galecto Biotech AB, UJN, HL: shareholders, personal fees – Galecto Biotech AB., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Objectives: Selvigaltin (GB1211), an orally available small molecule galectin-3 inhibitor developed as a treatment for liver fibrosis and cirrhosis, was evaluated to assess the effect of hepatic impairment on its pharmacokinetics and safety to address regulatory requirements., Methods: GULLIVER-2 was a Phase Ib/IIa three-part study. Parts 1 and 3 had single-dose, open-label designs assessing pharmacokinetics (plasma [total and unbound] and urine), safety, and tolerability of 100 mg oral selvigaltin in participants with moderate (Child-Pugh B, Part 1) or severe (Child-Pugh C, Part 3) hepatic impairment, compared with healthy-matched participants (n = 6 each)., Results: All participants received selvigaltin and completed the study. No adverse events were reported. The median time to reach maximum total plasma concentration following drug administration was of 3.49 and 4.00 h post-dose for Child-Pugh B and C participants, respectively; comparable with controls. Total plasma exposure was higher for participants with hepatic impairment compared with controls. Whilst maximum plasma concentration (C max ) was unaffected in Child-Pugh B participants, area under the plasma concentration-time curve from time zero to infinity (AUC ∞ ) increased by ~ 1.7-fold compared with controls, and half-life was prolonged (geometric mean 28.15 vs 16.38 h). In Child-Pugh C participants, C max increased by ~ 1.3-fold, AUC ∞ increased by ~ 1.5-fold, and half-life was prolonged (21.05 vs 16.14 h). No trend was observed in plasma unbound fractions or urinary excretion of unchanged selvigaltin in either group., Conclusion: Hepatic impairment increased selvigaltin exposure without safety concerns. These data can inform dose recommendations for future clinical programmes., Trial Registration: Clinicaltrials.gov NCT05009680., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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)., (© 2023. The Author(s).)

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 CCl 4 -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.

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 ( C ) values ranging from 0.6 to 3 h and a plasma half-life ( max ) 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.T 1/2 ) 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., Competing Interests: Conflict of interest: N. Hirani reports grants from Galecto Biotech, during the conduct of the study. Conflict of interest: A.C. MacKinnon reports personal fees from Galecto Biotech, outside the submitted work; and has a patent CA2,794,066 issued, a patent US13/832,672 issued and a patent WO/2014/067986 pending (all patents are fully owned by Galecto Biotech). Conflict of interest: L. Nicol reports grants from Galecto Biotech, during the conduct of the study; personal fees for lectures from Boehringer Ingelheim, outside the submitted work. Conflict of interest: P. Ford reports personal fees and nonfinancial support from Galecto, during the conduct of the study; and has a patent TD139 issued. Conflict of interest: H. Schambye reports personal fees from Galecto Inc, outside the submitted work; and has a patent WO/2016/180483 pending (fully owned by Galecto Biotech). Conflict of interest: A. Pedersen reports personal fees from Galecto Biotech, outside the submitted work. Conflict of interest: U.J. Nilsson has a patent CA2,794,066 issued, a patent US13/832,672 issued, a patent WO/2014/067986 pending, a patent WO/2005/113569 pending and a patent WO/2009/139719 pending (all patents are fully owned by Galecto Biotech). Conflict of interest: H. Leffler has a patent CA2,794,066 issued, a patent US13/832,672 issued, a patent WO/2014/067986 pending and a patent WO/2005/113569 pending (all patents are fully owned by Galecto Biotech). Conflict of interest: T. Sethi reports personal fees from Galecto Biotech, outside the submitted work; and has a patent CA2,794,066 issued, a patent US13/832,672 issued and a patent WO/2014/067986 pending (patents are fully owned by Galecto Biotech). Conflict of interest: S. Tantawi reports personal fees from Galecto Biotech, outside the submitted work. Conflict of interest: L. Gravelle reports personal fees from Galecto Biotech, outside the submitted work; and has a patent WO/2017/103109 pending (fully owned by Galecto Biotech). Conflict of interest: R.J. Slack reports personal fees from Galecto Biotech, outside the submitted work. Conflict of interest: R. Mills has nothing to disclose. Conflict of interest: U. Karmakar has nothing to disclose. Conflict of interest: D. Humphries has nothing to disclose. Conflict of interest: F. Zetterberg reports personal fees from Galecto Biotech, outside the submitted work. Conflict of interest: L. Keeling has nothing to disclose. Conflict of interest: L. Paul has nothing to disclose. Conflict of interest: P.L. Molyneaux has, via his institution, received industry-academic funding from AstraZeneca and has received speaker and consultancy fees from Boehringer Ingelheim and Hoffman-La Roche, outside the submitted work. Conflict of interest: F. Li has nothing to disclose. Conflict of interest: W. Funston has nothing to disclose. Conflict of interest: I.A. Forrest reports personal fees for consultancy and meeting attendance from Boehringer Ingelheim, personal fees for lectures and meeting attendance from Roche Ltd, outside the submitted work. Conflict of interest: A.J. Simpson has nothing to disclose. Conflict of interest: M.A. Gibbons has nothing to disclose. Conflict of interest: T.M. Maher has, via his institution, received industry-academic funding from AstraZeneca and GlaxoSmithKline R&D, and has received consultancy or speaker fees from AstraZeneca, Bayer, Blade Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Galapagos, GlaxoSmithKline R&D, Indalo, Novartis, Pliant, Respivant, Roche and Samumed., (Copyright ©ERS 2021.)

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. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/7/1480/F1.large.jpg., (©2019 American Association for Cancer Research.)

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.

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., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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.