TD139
目录号 : GC19350
TD139是galectin-3碳水化合物结合结构域的新型高亲和力抑制剂（Kd＝14nM）。
Cas No.:1450824-22-2
Sample solution is provided at 25 µL, 10mM.
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| Cell experiment [1]: | |
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Cell lines |
Mice Primary Alveolar Epithelial Cells |
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Preparation Method |
Primary alveolar epithelial cells from wild-type (WT) mice were plated and treated with transforming growth factor (TGF)-β1 in the presence or absence of 10 μM TD139 |
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Reaction Conditions |
10 μM TD139 |
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Applications |
TD139 blocked TGF-β1-induced phosphorylation of β-catenin. TD139 reduced TGF-β1-induced translocation of β-catenin to the nucleus, and most β-catenin was retained on the cell surface. |
| Animal experiment [1]: | |
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Animal models |
C57/Bl6 mice |
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Preparation Method |
Mice were given bleomycin intratracheally and then saline or 10 μg TD139 was instilled into the lungs on Days 18, 20, 22, and 24 and lungs were harvested on Day 26 |
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Dosage form |
10 μg TD139 on Days 18, 20, 22, and 24 |
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Applications |
In the lungs of WT mice treated with TD139 there was marked reduction in fibrosis and β-catenin activation accompanied by decreased galectin-3 expression. TD139 produced a significant decrease in total lung collagen, TD139 also decreased β-catenin activation in vivo as quantified, galectin-3 inhibition via TD139 can block the active fibrotic phase after bleomycin-induced lung injury. |
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References: [1]. Mackinnon AC, Gibbons MA, Farnworth SL, Leffler H, Nilsson UJ, Delaine T, Simpson AJ, Forbes SJ, Hirani N, Gauldie J, Sethi T. Regulation of transforming growth factor-β1-driven lung fibrosis by galectin-3. Am J Respir Crit Care Med. 2012 Mar 1;185(5):537-46. doi: 10.1164/rccm.201106-0965OC. Epub 2011 Nov 17. PMID: 22095546; PMCID: PMC3410728. |
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TD139 is a novel high-affinity inhibitor of the galectin-3 carbohydrate binding domain (Kd = 14 nM)[6].The antifibrotic potential of TD139 centres around the inhibition of the recruitment and expansion of Gal-3-secreting macrophages that drive local myofibroblast activation[7].
In Mice Primary Alveolar Epithelial Cells ,TD139 blocked TGF-β1-induced phosphorylation of β-catenin. TD139 reduced TGF-β1-induced translocation of β-catenin to the nucleus, and most β-catenin was retained on the cell surface[3].TD139 has been shown pre-clinically to exhibit effects on all of the key IPF cell types: modulating macrophage phenotype/Gal-3 expression and fibroblast activation, reducing the effects of key profibrotic growth factors that act on myofibroblasts, and inhibiting epithelial–mesenchymal transition[5,6].
In the lungs of WT mice treated with TD139 there was marked reduction in fibrosis and β-catenin activation accompanied by decreased galectin-3 expression. TD139 produced a significant decrease in total lung collagen, TD139 also decreased β-catenin activation in vivo as quantified, galectin-3 inhibition via TD139 can block the active fibrotic phase after bleomycin-induced lung injury[3].In mice, Inhibition of Gal3 by TD139 prevented the expression of proinflammatory cytokines in microglia, TD139 treatment ameliorated the clinical and histological manifestations of EAU[2].TD139 also suppressed microvascular thrombosis to protect the heart from myocardial ischaemia-reperfusion injury in ApoE-/- mice[1].
In clinical trials,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[4].
References:
[1]: Chen Y, Fu W, et,al. Galectin 3 enhances platelet aggregation and thrombosis via Dectin-1 activation: a translational study. Eur Heart J. 2022 Feb 15:ehac034. doi: 10.1093/eurheartj/ehac034. Epub ahead of print. PMID: 35165707.
[2]: Liu Y, Zhao C, et,al. Galectin-3 regulates microglial activation and promotes inflammation through TLR4/MyD88/NF-kB in experimental autoimmune uveitis. Clin Immunol. 2022 Mar;236:108939. doi: 10.1016/j.clim.2022.108939. Epub 2022 Feb 1. PMID: 35121106.
[3]: Mackinnon AC, Gibbons MA, et,al. Regulation of transforming growth factor-β1-driven lung fibrosis by galectin-3. Am J Respir Crit Care Med. 2012 Mar 1;185(5):537-46. doi: 10.1164/rccm.201106-0965OC. Epub 2011 Nov 17. PMID: 22095546; PMCID: PMC3410728.
[4]: Hirani N, MacKinnon AC, et,al. Target inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis. Eur Respir J. 2021 May 27;57(5):2002559. doi: 10.1183/13993003.02559-2020. Erratum in: Eur Respir J. 2022 Apr 14;59(4): PMID: 33214209; PMCID: PMC8156151.
[5]: N. Hirani, L. Nicol, A.C. et,al. TD139, A Novel Inhaled Galectin-3 Inhibitor for The Treatment of Idiopathic Pulmonary Fibrosis (IPF). Results from The First in (IPF) Patients Study., QJM: An International Journal of Medicine, Volume 109, Issue suppl_1, September 2016, Page S16, https://doi.org/10.1093/qjmed/hcw127.003
[6]: Delaine T, Collins P, et,al. Galectin-3-Binding Glycomimetics that Strongly Reduce Bleomycin-Induced Lung Fibrosis and Modulate Intracellular Glycan Recognition. Chembiochem. 2016 Sep 15;17(18):1759-70. doi: 10.1002/cbic.201600285. Epub 2016 Aug 12. PMID: 27356186.
[7]: MacKinnon AC, Farnworth SL, et,al. Regulation of alternative macrophage activation by galectin-3. J Immunol. 2008 Feb 15;180(4):2650-8. doi: 10.4049/jimmunol.180.4.2650. PMID: 18250477.
TD139 是半乳糖凝集素 3 碳水化合物结合域的新型高亲和力抑制剂 (Kd = 14 nM)[6]。TD139 的抗纤维化潜力主要集中在抑制募集和扩张驱动局部肌成纤维细胞活化的 Gal-3 分泌巨噬细胞[7]。
在小鼠原代肺泡上皮细胞中，TD139 阻断了 TGF-β1 诱导的 β-连环蛋白磷酸化。 TD139 减少了 TGF-β1 诱导的 β-catenin 向细胞核的易位，并且大部分 β-catenin 保留在细胞表面[3]。TD139 已在临床前显示对所有细胞均有影响关键 IPF 细胞类型:调节巨噬细胞表型/Gal-3 表达和成纤维细胞活化，减少作用于肌成纤维细胞的关键促纤维化生长因子的作用，抑制上皮-间质转化[5,6] .
在用 TD139 处理的 WT 小鼠的肺中，纤维化和 β-连环蛋白活化明显减少，同时半乳糖凝集素 3 表达减少。 TD139 显着降低了肺部胶原蛋白总量，TD139 还降低了体内 β-catenin 的量化激活，通过 TD139 抑制 galectin-3 可以阻断博来霉素诱导的肺损伤后的活性纤维化阶段[3] .在小鼠中，TD139 抑制 Gal3 阻止了小胶质细胞中促炎细胞因子的表达，TD139 治疗改善了 EAU 的临床和组织学表现[2]。TD139 还抑制微血管血栓形成以保护心脏免受心肌损伤ApoE-/-小鼠缺血再灌注损伤[1].
在临床试验中，TD139 在健康受试者和 IPF 患者中是安全且耐受性良好的。它被证明可以抑制支气管肺泡灌洗巨噬细胞上的 Gal-3 表达，并以协同方式减少与 IPF 进展相关的血浆生物标志物[4]。
| Cas No. | 1450824-22-2 | SDF | |
| Canonical SMILES | O[C@H]([C@@H](N1N=NC(C2=CC=CC(F)=C2)=C1)[C@H]([C@@H](CO)O3)O)[C@@H]3S[C@H]4[C@@H]([C@@H](N5N=NC(C6=CC=CC(F)=C6)=C5)[C@H]([C@@H](CO)O4)O)O | ||
| 分子式 | C28H30F2N6O8S | 分子量 | 648.64 |
| 溶解度 | DMSO : 50 mg/mL (77.08 mM);Ethanol : ≥ 3.33 mg/mL (5.13 mM);Water : < 0.1 mg/mL (insoluble) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.5417 mL | 7.7084 mL | 15.4169 mL |
| 5 mM | 0.3083 mL | 1.5417 mL | 3.0834 mL |
| 10 mM | 0.1542 mL | 0.7708 mL | 1.5417 mL |
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Target inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis
Eur Respir J2021 May 27;57(5):2002559.PMID: 33214209DOI: 10.1183/13993003.02559-2020
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 max) values ranging from 0.6 to 3 h and a plasma half-life (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.
Single-Cell Reconstruction of Progression Trajectory Reveals Intervention Principles in Pathological Cardiac Hypertrophy
Circulation2020 May 26;141(21):1704-1719.PMID: 32098504DOI: 10.1161/CIRCULATIONAHA.119.043053
Background: Pressure overload-induced pathological cardiac hypertrophy is a common predecessor of heart failure, the latter of which remains a major cardiovascular disease with increasing incidence and mortality worldwide. Current therapeutics typically involve partially relieving the heart's workload after the onset of heart failure. Thus, more pathogenesis-, stage-, and cell type-specific treatment strategies require refined dissection of the entire progression at the cellular and molecular levels.
Methods: By analyzing the transcriptomes of 11,492 single cells and identifying major cell types, including both cardiomyocytes and noncardiomyocytes, on the basis of their molecular signatures, at different stages during the progression of pressure overload-induced cardiac hypertrophy in a mouse model, we characterized the spatiotemporal interplay among cell types, and tested potential pharmacological treatment strategies to retard its progression in vivo.
Results: We illustrated the dynamics of all major cardiac cell types, including cardiomyocytes, endothelial cells, fibroblasts, and macrophages, as well as those of their respective subtypes, during the progression of disease. Cellular crosstalk analysis revealed stagewise utilization of specific noncardiomyocytes during the deterioration of heart function. Specifically, macrophage activation and subtype switching, a key event at middle-stage of cardiac hypertrophy, was successfully targeted by Dapagliflozin, a sodium glucose cotransporter 2 inhibitor, in clinical trials for patients with heart failure, as well as TD139 and Arglabin, two anti-inflammatory agents new to cardiac diseases, to preserve cardiac function and attenuate fibrosis. Similar molecular patterns of hypertrophy were also observed in human patient samples of hypertrophic cardiomyopathy and heart failure.
Conclusions: Together, our study not only illustrated dynamically changing cell type crosstalk during pathological cardiac hypertrophy but also shed light on strategies for cell type- and stage-specific intervention in cardiac diseases.
Regulation of transforming growth factor-β1-driven lung fibrosis by galectin-3
Am J Respir Crit Care Med2012 Mar 1;185(5):537-46.PMID: 22095546DOI: 10.1164/rccm.201106-0965OC
Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic dysregulated response to alveolar epithelial injury with differentiation of epithelial cells and fibroblasts into matrix-secreting myofibroblasts resulting in lung scaring. The prognosis is poor and there are no effective therapies or reliable biomarkers. Galectin-3 is a β-galactoside binding lectin that is highly expressed in fibrotic tissue of diverse etiologies.
Objectives: To examine the role of galectin-3 in pulmonary fibrosis.
Methods: We used genetic deletion and pharmacologic inhibition in well-characterized murine models of lung fibrosis. Further mechanistic studies were performed in vitro and on samples from patients with IPF.
Measurements and main results: Transforming growth factor (TGF)-β and bleomycin-induced lung fibrosis was dramatically reduced in mice deficient in galectin-3, manifest by reduced TGF-β1-induced EMT and myofibroblast activation and collagen production. Galectin-3 reduced phosphorylation and nuclear translocation of β-catenin but had no effect on Smad2/3 phosphorylation. A novel inhibitor of galectin-3, TD139, blocked TGF-β-induced β-catenin activation in vitro and in vivo and attenuated the late-stage progression of lung fibrosis after bleomycin. There was increased expression of galectin-3 in the bronchoalveolar lavage fluid and serum from patients with stable IPF compared with nonspecific interstitial pneumonitis and controls, which rose sharply during an acute exacerbation suggesting that galectin-3 may be a marker of active fibrosis in IPF and that strategies that block galectin-3 may be effective in treating acute fibrotic exacerbations of IPF.
Conclusions: This study identifies galectin-3 as an important regulator of lung fibrosis and provides a proof of principle for galectin-3 inhibition as a potential novel therapeutic strategy for IPF.
Molecular mechanism of interspecies differences in the binding affinity of TD139 to Galectin-3
Glycobiology2021 Nov 18;31(10):1390-1400.PMID: 34228782DOI: 10.1093/glycob/cwab072
Galectin-3 (Gal-3), a β-galactoside-binding lectin, has been implicated in a plethora of pathological disorders including fibrosis, inflammation, cancer and metabolic diseases. TD139-a thio-digalactoside inhibitor developed by Galecto Biotech as a potential therapeutic for idiopathic pulmonary fibrosis-is the most advanced small-molecule Gal-3 inhibitor in clinical studies. It binds to human Gal-3 with high affinity but has lower affinity towards mouse and rat homologs, which is also manifested in the differential inhibition of Gal-3 function. Using biophysical methods and high-resolution X-ray co-crystal structures of TD139 and Gal-3 proteins, we demonstrate that a single amino acid change corresponding to A146 in human Gal-3 is sufficient for the observed reduction in the binding affinity of TD139 in rodents. Site-directed mutagenesis of A146V (in human Gal-3) and V160A (in mouse Gal-3) was sufficient to interchange the affinities, mainly by affecting the off rates of the inhibitor binding. In addition, molecular dynamics simulations of both wild-type and mutant structures revealed the sustained favorable noncovalent interactions between the fluorophenyl ring and the active site A146 (human Gal-3 and mouse V160A) that corroborate the finding from biophysical studies. Current findings have ramifications in the context of optimization of drug candidates against Gal-3.
Efficient synthesis of a galectin inhibitor clinical candidate (TD139) using a Payne rearrangement/azidation reaction cascade
Org Biomol Chem2020 May 27;18(20):3903-3907.PMID: 32400847DOI: 10.1039/d0ob00910e
Selective galectin inhibitors are valuable research tools and could also be used as drug candidates. In that context, TD139, a thiodigalactoside galectin-3 inhibitor, is currently being evaluated clinically for the treatment of idiopathic pulmonary fibrosis. Herein, we describe a new strategy for the preparation of TD139. Starting from inexpensive levoglucosan, we used a rarely employed reaction cascade: Payne rearrangement/azidation process leading to 3-azido-galactopyranose. The latter intermediate was efficiently converted into TD139 in a few simple and practical steps.