Fredrik Zetterberg - Academia.edu (original) (raw)

Uploads

Papers by Fredrik Zetterberg

Gastric Cancer, 2021

Aberrant activation of the WNT/β-catenin and STAT3 signaling pathways plays a critical role in ca... more Aberrant activation of the WNT/β-catenin and STAT3 signaling pathways plays a critical role in cancer progression. However, direct targeting of these pathways as an anti-cancer therapeutic approach needs to be reconsidered due to its serious side effects. Here, we demonstrate that overexpression of WNT induces STAT3 activation in a galectin-3-dependent manner. We investigated how galectin-3 mediates the crosstalk between WNT/β-catenin and STAT3 signaling and whether inhibition of galectin-3 can reduce gastric cancer. The molecular mechanisms were analyzed by biochemical assays using cultured gastric cancer cells, patient tissues, and genetically engineered mice. Moreover, we confirm of therapeutic effects of GB1107, a cell-penetrating galectin-3 specific inhibitor, using orthotopic gastric cancer-bearing mice Increased levels of galectin-3 and STAT3 phosphorylation were detected in the stomach tissues of WNT1-overexpressing mouse models. Also, high expression levels and co-localization of β-catenin, pSTAT3, and galectin-3 in patients with advanced gastric cancer were correlated with a poorer prognosis. Galectin-3 depletion significantly decreased STAT3 Tyr705 phosphorylation, which regulates its nuclear localization and transcriptional activation. A peptide of galectin-3 (Y45-Q48) directly bound to the STAT3 SH2 domain and enhanced its phosphorylation. GB1107, a specific membrane-penetrating inhibitor of galectin-3, significantly reduced the activation of both STAT3 and β-catenin and inhibited tumor growth in orthotopic gastric cancer-bearing mice. We propose that galectin-3 mediates the crosstalk between the WNT and STAT3 signaling pathways. Therefore GB1107, a galectin-3-specific inhibitor, maybe a potent agent with anti-gastric cancer activity. Further studies are needed for its clinical application in gastric cancer therapy.

European Journal of Medicinal Chemistry, 2021

We have obtained the X-ray crystal structure of the galectin-8 N-terminal domain (galectin-8N) wi... more We have obtained the X-ray crystal structure of the galectin-8 N-terminal domain (galectin-8N) with a previously reported quinoline-galactoside ligand at a resolution of 1.6 Å. Based on this X-ray structure, a collection of galactosides derivatised at O3 with triazole, benzimidazole, benzothiazole, and benzoxazole moieties were designed and synthesised. This led to the discovery of a 3-O-(N-methylbenzimidazolylmethyl)-galactoside with a Kd of 1.8 μM for galectin-8N, the most potent selective synthetic galectin-8N ligand to date. Molecular dynamics simulations showed that benzimidazole-galactoside derivatives bind the non-conserved amino acid Gln47, accounting for the higher selectivity for galectin-8N. Galectin-8 is a carbohydrate-binding protein that plays a key role in pathological lymphangiogenesis, modulation of the immune system, and autophagy. Thus, the benzimidazole-derivatised galactosides represent promising compounds for studies of the pathological implications of galectin-8, as well as a starting point for the development of anti-tumour and anti-inflammatory therapeutics targeting galectin-8.

European Respiratory Journal, 2020

Galectin (Gal)-3 is a profibrotic β-galactoside-binding lectin that plays a key role in the patho... more 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 l...

Journal of Medicinal Chemistry, 2019

Glycomimetic drugs have attracted increasing interest as unique targeting vectors or surrogates f... more Glycomimetic drugs have attracted increasing interest as unique targeting vectors or surrogates for endogenous biomolecules. However, it's generally difficult to determine the in vivo pharmacokinetic profile of these compounds. In this work, two galectin-3 inhibitors were radiolabeled with fluorine-18 and used as surrogate PET tracers of TD139 and GB1107. Both compounds are promising drugs for clinical applications. In vivo evaluation revealed that both surrogates strongly differed in respect to their biodistribution profile. The disaccharide (TD139 surrogate) was rapidly eliminated from blood while the monosaccharide (GB1107 surrogate) showed no sign of excretion. The data obtained allowed us to infer the different in vivo fate of TD139 and GB1107 and rationalize how different administration routes could boost efficacy. Whereas the fast excretion profile of the TD139 surrogate indicated that systemic application of disaccharides is unfavorable, the extended biological half-life of the GB1107 surrogate indicated that systemic administration is possible for monosaccharides.

RSC Advances, 2018

A series of 3-triazole-thiogalactosides and 3,3′-triazole-thiodigalactosides substituted with dif... more A series of 3-triazole-thiogalactosides and 3,3′-triazole-thiodigalactosides substituted with different five-membered heterocycles at the C-4 triazole position were found to have high selectivity for galectin-1.

MedChemComm, 2019

Galactopyranosides with aryl-aminopyrimidine moieties at O3 inhibit the tumor and immunity-relate... more Galactopyranosides with aryl-aminopyrimidine moieties at O3 inhibit the tumor and immunity-related galectin-3 with high selectivity over other galectins.

Scientific Reports, 2019

Galectin-3 is a carbohydrate binding protein which has important roles in cancer and immunity. Po... more 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. The galectin family of carbohydrate binding proteins have gained increasing interest as therapeutic targets in several diseases, such as chronic inflammation and cancer 1-4. Galectins are soluble proteins synthesized on free ribosomes in the cytosol. Even though they lack the classical characteristics of secreted proteins, they are rapidly translocated to the extracellular space through a yet unknown pathway 5. Once in the extracellular environment, the galectins are exposed to a large variety of glycan structures, where they recognize and bind specific β-galactosides. As some galectins are able to form multivalent structures or are multivalent in nature, they are able to cross-link glycoconjugates and form lattices. Formation of galectin/glycoconjugate lattices on the plasma membrane has been observed to influence the expression time, localization, and activity of several cell surface receptors, thus influencing numerous biological functions such as cell signaling, cell migration, and cell adherence 5,6. Furthermore, galectins can quickly (within minutes) be recycled back to the inside of cells trough the endocytic pathway, regulating sorting of both soluble and membrane bound glycoconjugates 5,7. Apart from the extracellular activities of the galectin family, mediated through glycan binding, galectins also play important roles in the intracellular compartments. Several studies have reported that galectins may influence cell signaling by interacting with signaling proteins in the cytosol, e.g. RAS proteins and β-catenin, and RNA splicing through binding of components of the spliceosome complex in the nucleus 8-12. As complex glycans are not found in the intracellular compartment, these activities are most likely mediated trough protein-protein interactions. Interestingly, however, several of these reported intracellular activates are inhibited by molecules interacting with the galectin carbohydrate binding site, such as lactose 8,10,13. Additionally, galectins play an important role at the interface between the cytosolic and intravesicular compartments by monitoring the integrity of vesicular membranes. It is now well established that several galectins (e.g. galectin-3 and-8 in particular) accumulate around disrupted vesicles by binding to exposed glycan structures and induce clearance of the damaged organelles by selective autophagy 14-20. The diverse roles of the galectins on a cellular level have consequences for several physiological

Cancer Research, 2019

A novel and orally active galectin-3 antagonist inhibits lung adenocarcinoma growth and metastasi... more A novel and orally active galectin-3 antagonist inhibits lung adenocarcinoma growth and metastasis and augments response to PD-L1 blockade.

Journal of medicinal chemistry, Jan 28, 2017

Symmetrical and asymmetrical fluorinated phenyltriazolyl-thiodigalactoside derivatives have been ... more Symmetrical and asymmetrical fluorinated phenyltriazolyl-thiodigalactoside derivatives have been synthesized and evaluated as inhibitors of galectin-1 and galectin-3. Systematic tuning of the phenyltriazolyl-thiodigalactosides' fluoro-interactions with galectin-3 led to the discovery of inhibitors with exceptional affinities (Kd down to 1-2 nM) in symmetrically substituted thiodigalactosides, as well as unsurpassed combination of high affinity (Kd 7.5 nM) and selectivity (46-fold) over galectin-1 for asymmetrical thiodigalactosides carrying one trifluorphenyltriazole and one coumaryl moiety. Studies of the inhibitor-galectin-complexes with isothermal titration calorimetry and X-ray crystallography revealed the importance of fluoro-amide interaction for affinity and for selectivity. Finally, the high affinity of the discovered inhibitors required two competitive titration assay tools to be developed: a new high affinity fluorescent probe for competitive fluorescent polarization a...

Future medicinal chemistry, 2013

Recently, we reported ethyl nicotinates as antagonists of the P2Y12 receptor, which is an importa... more Recently, we reported ethyl nicotinates as antagonists of the P2Y12 receptor, which is an important target in antiplatelet therapies. A potential liability of these compounds was their generally high in vivo clearance due to ethyl ester hydrolysis. Shape and electrostatic similarity matching was used to select five-membered heterocycles to replace the ethyl ester functionality. The 5-methyl and 5-ethyl-oxazole bioisosteres retained the sub-micromolar potency levels of the parent ethyl esters. Many oxazoles showed a higher CYP450 dependent microsomal metabolism than the corresponding ethyl esters. Structure activity relationship investigations supported by ab initio calculations suggested that a correctly positioned alkyl substituent and a strong hydrogen bond acceptor were necessary structural motifs for binding. In rat pharmacokinetics, the low clearance was retained upon replacement of an ethyl ester with a 5-ethyl-oxazole. The use of shape and electrostatic similarity led to the ...