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Università della Svizzera italiana

The novel TORC1/2 kinase inhibitor PQR620 has anti-tumor activity in lymphomas as a single agent and in combination with venetoclax

Tarantelli, Chiara ; Gaudio, Eugenio ; Hillmann, Petra ; Spriano, Filippo ; Sartori, Giulio ; Aresu, Luca ; Cascione, Luciano ; Rageot, Denise ; Kwee, Ivo ; Beaufils, Florent ; Zucca, Emanuele ; Stathis, Anastasios ; Wymann, Matthias P. ; Cmiljanovic, Vladimir ; Fabbro, Doriano ; Bertoni, Francesco

In: Cancers, 2019, vol. 11, no. 6, p. 775

The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling cascade is an important therapeutic target for lymphomas. Rapamycin-derivates as allosteric mTOR complex 1 (TORC1) inhibitors have shown moderate preclinical and clinical anti-lymphoma activity. Here, we assessed the anti-tumor activity of PQR620, a novel brain penetrant dual TORC1/2 inhibitor, in 56...

Université de Fribourg

PI3Kγ activity in leukocytes promotes adipose tissue inflammation and early-onset insulin resistance during obesity

Breasson, Ludovic ; Becattini, Barbara ; Sardi, Claudia ; Molinaro, Angela ; Zani, Fabio ; Marone, Romina ; Botindari, Fabrizio ; Bousquenaud, Mélanie ; Rüegg, Curzio ; Wymann, Matthias P. ; Solinas, Giovanni

In: Science Signaling, 2017, vol. 10, no. 488, p. eaaf2969

The phosphoinositide 3-kinase γ (PI3Kγ) plays a major role in leukocyte recruitment during acute inflammation and has been proposed to inhibit classical macrophage activation by driving immunosuppressive gene expression. PI3Kγ plays an important role in diet-induced obesity and insulin resistance. In seeking to determine the underlying molecular mechanisms, we showed that PI3Kγ action in...

Université de Fribourg

Cell-Permeant and photocleavable chemical inducer of dimerization

Zimmermann, Mirjam ; Cal, Ruben ; Janett, Elia ; Hoffmann, Viktor ; Bochet, Christian G. ; Constable, Edwin ; Beaufils, Florent ; Wymann, Matthias P.

In: Angewandte Chemie International Edition, 2014, vol. 53, no. 18, p. 4717–4720

Chemical inducers of dimerization (CIDs) have been developed to orchestrate protein dimerization and translocation. Here we present a novel photocleavable HaloTag- and SNAP-tag-reactive CID (MeNV-HaXS) with excellent selectivity and intracellular reactivity. Excitation at 360 nm cleaves the methyl-6-nitroveratryl core of MeNV-HaXS. MeNV-HaXS covalently links HaloTag- and SNAP-tag fusion...

Université de Fribourg

Inhibition of phosphoinositide 3-kinase γ attenuates inflammation, obesity, and cardiovascular risk factors

Wymann, Matthias P. ; Solinas, Giovanni

In: Annals of the New York Academy of Sciences, 2013, vol. 1280, p. 44-47

Phosphoinositide 3-kinase γ (PI3Kγ) plays a central role in inflammation, allergy, cardiovascular, and metabolic disease. Obesity is accompanied by chronic, low-grade inflammation. As PI3Kγ plays a major role in leukocyte recruitment, targeting of PI3Kγ has been considered to be a strategy for attenuating progression of obesity to insulin resistance and type 2 diabetes. Indeed, PI3Kγ null...

Université de Fribourg

PI3Kγ within a nonhematopoietic cell type negatively regulates diet-induced thermogenesis and promotes obesity and insulin resistance

Becattini, Barbara ; Marone, Romina ; Zani, Fabio ; Arsenijevic, Denis ; Seydoux, Josiane ; Montani, Jean-Pierre ; Dulloo, Abdul G. ; Thorens, Bernard ; Preitner, Frédéric ; Wymann, Matthias P. ; Solinas, Giovanni

In: Proceedings of the National Academy of Sciences of the United States of America, 2011, vol. 108, no. 42, p. E854-E863

Obesity is associated with a chronic low-grade inflammation, and specific antiinflammatory interventions may be beneficial for the treatment of type 2 diabetes and other obesity-related diseases. The lipid kinase PI3Kγ is a central proinflammatory signal transducer that plays a major role in leukocyte chemotaxis, mast cell degranulation, and endothelial cell activation. It was also reported that...

Université de Fribourg

Lipid signalling in disease

Wymann, Matthias P. ; Schneiter, Roger

In: Nature Reviews Molecular Cell Biology, 2008, vol. 9, p. 162-176

Université de Fribourg

Living with Lethal PIP3 Levels: Viability of Flies Lacking PTEN Restored by a PH Domain Mutation in Akt/PKB

Stocker, Hugo ; Andjelkovic, Mirjana ; Oldham, Sean ; Laffargue, Muriel ; Wymann, Matthias P. ; Hemmings, Brian A. ; Hafen, Ernst

In: Science, 2002, vol. 15, no. 5562, p. 2088 - 2091

The phosphoinositide phosphatase PTEN is mutated in many human cancers. Although the role of PTEN has been studied extensively, the relative contributions of its numerous potential downstream effectors to deregulated growth and tumorigenesis remain uncertain. We provide genetic evidence in Drosophila melanogaster for the paramount importance of the protein kinase Akt [also called protein...

Université de Fribourg

Weakening link to colorectal cancer ?

Barbier, Maryse ; Attoub, S. ; Calvez, Ronan ; Laffargue, Muriel ; Jarry, A. ; Mareel, M. ; Altruda, F. ; Gespach, C. ; Wu, D. ; Lu, B. ; Hirsch, E. ; Wymann, Matthias P.

In: Nature, 2001, vol. 413, p. 796

The catalytic α-subunit of the enzyme phosphatidylinositol-3-OH kinase (PI(3)Kα) relays signals from G- protein-coupled receptors at the cell membrane and mediates leukocyte responses to chemokines and chemoattractants1, 2, ³. Sasaki et al.⁴ report that mice that cannot produce PI(3)Kα have a high incidence of colorectal carcinomas, causing weight loss and...

Université de Fribourg

The direct effect of leptin on skeletal muscle thermogenesis is mediated by substrate cycling between de novo lipogenesis and lipid oxidation

Solinas, Giovanni ; Summermatter, Serge ; Mainieri, Davide ; Gubler, Marcel ; Pirola, Luciano ; Wymann, Matthias P. ; Rusconi, Sandro ; Montani, Jean-Pierre ; Seydoux, Josiane

In: FEBS Letters, 2004, vol. 577, no. 3, p. 539-544

We report here studies that integrate data of respiration rate from mouse skeletal muscle in response to leptin and pharmacological interference with intermediary metabolism, together with assays for phosphatidylinositol 3-kinase (PI3K) and AMP- activated protein kinase (AMPK). Our results suggest that the direct effect of leptin in stimulating thermogenesis in skeletal muscle is mediated by...