Synthesis, Structure–Activity Relationships, and In Vivo Evaluation of Novel Tetrahydropyran-Based Thiodisaccharide Mimics as Galectin-3 Inhibitors

Xu, Li; Hartz, Richard A.; Beno, Brett R.; Ghosh, Kaushik; Shukla, Jinal K.; Kumar, Amit; Patel, Dipal; Kalidindi, Narasimharaju; Lemos, Nadine; Gautam, Shashyendra Singh; Kumar, Anoop; Ellsworth, Bruce A.; Shah, Devang; Sale, Harinath; Cheng, Dong; Regueiro‐Ren, Alicia

doi:10.1021/acs.jmedchem.0c02001

Cited by 18 publications

(22 citation statements)

References 50 publications

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“…This is most likely due to the difference in human and mouse protein sequence 144–150, in particular position 146, which is an alanine in human galectin-3 and a sterically more demanding valine (V160) in mouse galectin-3 . A recent publication showcasing X-ray structures on a related series further supports this hypothesis. , …”

Section: Resultsmentioning

confidence: 97%

Discovery and Optimization of the First Highly Effective and Orally Available Galectin-3 Inhibitors for Treatment of Fibrotic Disease

Zetterberg¹,

MacKinnon²,

Brimert

et al. 2022

J. Med. Chem.

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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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Section: Resultsmentioning

confidence: 97%

Discovery and Optimization of the First Highly Effective and Orally Available Galectin-3 Inhibitors for Treatment of Fibrotic Disease

Zetterberg¹,

MacKinnon²,

Brimert

et al. 2022

J. Med. Chem.

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“…The diverse spectrum of TDG C-3/C-3′ phenyl substituents with antagonistic electronic effects on the phenyl ring was primarily selected on the basis of a comprehensive report by Sörme et al where 4-nitro-, 4-aceto-, 4-cyano, and 4-( t -butyl) substituents increased the overall affinity of LacNAc-based glycomimetics compared to the reference phenyl substituent. In addition, a strongly galectin-inhibiting thienyl moiety was also included in this study, along with two 4-halogen substituents (fluoro and bromo). , All of these substituents were cross-referenced with our previous studies due to the aforementioned linker variance. , Though there are existing SAR studies with triazole-linked substituents in the literature, − their conclusions are not fully transferable to the present compounds due to the different linkers used. Here, the methylene insertion between the carbohydrate moiety and the triazole ring extends the linker by two additional atoms, which brings its higher flexibility in the galectin binding pocket.…”

Section: Resultsmentioning

confidence: 99%

Glycopolymers Decorated with 3-O-Substituted Thiodigalactosides as Potent Multivalent Inhibitors of Galectin-3

et al. 2022

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Galectin-3 (Gal-3) participates in many cancer-related metabolic processes. The inhibition of overexpressed Gal-3 by, e.g., β-galactoside-derived inhibitors is hence promising for cancer treatment. The multivalent presentation of such inhibitors on a suitable biocompatible carrier can enhance the overall affinity to Gal-3 and favorably modify the interaction with Gal-3-overexpressing cells. We synthesized a library of C-3 aryl-substituted thiodigalactoside inhibitors and their multivalent N-(2-hydroxypropyl)methacrylamide (HPMA)-based counterparts with two different glycomimetic contents. Glycopolymers with a higher content of glycomimetic exhibited a higher affinity to Gal-3 as assessed by ELISA and biolayer interferometry. Among them, four candidates (with 4-acetophenyl, 4-cyanophenyl, 4-fluorophenyl, and thiophen-3-yl substitution) were selected for further evaluation in cancer-related experiments in cell cultures. These glycopolymers inhibited Gal-3-induced processes in cancer cells. The cyanophenyl-substituted glycopolymer exhibited the strongest antiproliferative, antimigratory, antiangiogenic, and immunoprotective properties. The prepared glycopolymers appear to be prospective modulators of the tumor microenvironment applicable in the therapy of Gal-3-associated cancers.

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“…For example, cyclodextrins, cyclic peptides, calixarenes and glycophanes have been designed from β-L [ 129 ]. Various lactosides and glycomimetics can be used to design high affinity and selective galectin antagonists, especially for human Gal-1 and Gal-3 which are largely studied [ 130 , 131 , 132 , 133 , 134 , 135 ]. Gal-3 is an attractive anticancer target, notably for breast and endometrial cancers [ 136 , 137 , 138 ].…”

Section: Tim-3/gal-9 Signaling Blockade With α/β-Lactosementioning

confidence: 99%

Modulation of the Gal-9/TIM-3 Immune Checkpoint with α-Lactose. Does Anomery of Lactose Matter?

Bailly

Thuru

Quesnel

2021

Cancers

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The disaccharide lactose is an excipient commonly used in pharmaceutical products. The two anomers, α- and β-lactose (α-L/β-L), differ by the orientation of the C-1 hydroxyl group on the glucose unit. In aqueous solution, a mutarotation process leads to an equilibrium of about 40% α-L and 60% β-L at room temperature. Beyond a pharmaceutical excipient in solid products, α-L has immuno-modulatory effects and functions as a major regulator of TIM-3/Gal-9 immune checkpoint, through direct binding to the β-galactoside-binding lectin galectin-9. The blockade of the co-inhibitory checkpoint TIM-3 expressed on T cells with anti-TIM-3 antibodies represents a promising approach to combat different onco-hematological diseases, in particular myelodysplastic syndromes and acute myeloid leukemia. In parallel, the discovery and development of anti-TIM-3 small molecule ligands is emerging, including peptides, RNA aptamers and a few specifically designed heterocyclic molecules. An alternative option consists of targeting the different ligands of TIM-3, notably Gal-9 recognized by α-lactose. Modulation of the TIM-3/Gal-9 checkpoint can be achieved with both α- and β-lactose. Moreover, lactose is a quasi-pan-galectin ligand, capable of modulating the functions of most of the 16 galectin molecules. The present review provides a complete analysis of the pharmaceutical and galectin-related biological functions of (α/β)-lactose. A focus is made on the capacity of lactose and Gal-9 to modulate both the TIM-3/Gal-9 and PD-1/PD-L1 immune checkpoints in oncology. Modulation of the TIM-3/Gal-9 checkpoint is a promising approach for the treatment of cancers and the role of lactose in this context is discussed. The review highlights the immuno-regulatory functions of lactose, and the benefit of the molecule well beyond its use as a pharmaceutical excipient.

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Synthesis, Structure–Activity Relationships, and In Vivo Evaluation of Novel Tetrahydropyran-Based Thiodisaccharide Mimics as Galectin-3 Inhibitors

Cited by 18 publications

References 50 publications

Discovery and Optimization of the First Highly Effective and Orally Available Galectin-3 Inhibitors for Treatment of Fibrotic Disease

Discovery and Optimization of the First Highly Effective and Orally Available Galectin-3 Inhibitors for Treatment of Fibrotic Disease

Glycopolymers Decorated with 3-O-Substituted Thiodigalactosides as Potent Multivalent Inhibitors of Galectin-3

Modulation of the Gal-9/TIM-3 Immune Checkpoint with α-Lactose. Does Anomery of Lactose Matter?

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