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Brasca M.G.,Nerviano Medical science Srl | Albanese C.,Nerviano Medical science Srl | Alzani R.,Nerviano Medical science Srl | Amici R.,Congenia S.r.l. | And 18 more authors.
Bioorganic and Medicinal Chemistry | Year: 2010

We have recently reported CDK inhibitors based on the 6-substituted pyrrolo[3,4-c]pyrazole core structure. Improvement of inhibitory potency against multiple CDKs, antiproliferative activity against cancer cell lines and optimization of the physico-chemical properties led to the identification of highly potent compounds. Compound 31 (PHA-793887) showed good efficacy in the human ovarian A2780, colon HCT-116 and pancreatic BX-PC3 carcinoma xenograft models and was well tolerated upon daily treatments by iv administration. It was identified as a drug candidate for clinical evaluation in patients with solid tumors. © 2010 Elsevier Ltd. All rights reserved.


Nowak-Sliwinska P.,Ecole Polytechnique Federale de Lausanne | Storto M.,Congenia Srl | Cataudella T.,DAC Research | Ballini J.-P.,Ecole Polytechnique Federale de Lausanne | And 5 more authors.
Microvascular Research | Year: 2012

We investigated the anti-angiogenic properties of GNX-686, a newly identified maleimide-based small molecule. In vitro studies on HUVEC showed that GNX-686 inhibited cell growth with an ED 50 of 20-25μM, while human HeLa tumor cells and non-transformed embryonic mouse fibroblasts were less sensitive for the drug. More importantly, at 4μM, a concentration that was non-toxic to any cell in culture, GNX-686 showed a significant inhibitory effect on tube formation by HUVEC, indicating a profound anti-angiogenic activity. Angiogenesis inhibition was subsequenly tested in the chorioallantoic membrane (CAM) of the chicken embryo. A significant angiostatic activity was observed in the CAM model, and results were compared with the effect of bevacizumab, a well known and clinically used VEGF inhibitor. Under our experimental conditions, GNX-686 was found to be as effective as bevacizumab, significantly changing the morphology of the vascular network, as illustrated and quantified by the relative number of branching points and the relative mean mesh size of the vascular network. In another in vivo model of neovascularization, the mouse retinopathy of prematurity (ROP), the vascular network of GNX-686-treated mice was significantly altered, reducing the density of the retinal microvasculature, as compared to the control retinas. Immunohistochemical processing of the GNX-686 treated (4μM) eyes showed over 50% reduction of the number of cell nuclei associated with neovasculature, as compared to the control-treated eye. Taken together these results demonstrate that GNX-686 is a promising anti-angiogenic compound that could be developed for the treatment of diseases characterized by aberrant angiogenesis such as ocular pathologies and cancer. © 2011 Elsevier Inc.


Marenzi G.,University of Milan | Giorgio M.,Italian National Cancer Institute | Trinei M.,Italian National Cancer Institute | Trinei M.,Congenia Srl | And 10 more authors.
American Journal of Cardiology | Year: 2010

In patients with ST-segment elevation acute myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI), abrupt reperfusion can induce myocardial injury and apoptotic cell death. Reperfusion-induced myocardial damage, however, cannot be easily evaluated in clinical practice because of the lack of specific biomarkers. Cytochrome c, a mitochondrial protein, is released on reperfusion into the cytosol, where it triggers the apoptotic process. It can reach the external fluid and circulating blood when cell rupture occurs. We measured the cytochrome c circulating levels in patients with STEMI undergoing pPCI, and correlated them with the clinical signs of myocardial necrosis and reperfusion. The plasma creatine kinase-MB mass and serum cytochrome c (enzyme-linked immunosorbent assay method) were serially measured in 55 patients with STEMI undergoing pPCI. The angiographic and electrocardiographic signs of myocardial reperfusion were also assessed. Cytochrome c transiently increased in all patients with STEMI, with a curve that paralleled that of creatine kinase-MB. A significant relation was found between the peak values of the 2 biomarkers (R = 0.35, p = 0.01) and between the areas under the 2 curves (R = 0.33, p = 0.02). The creatine kinase-MB peak value correlated significantly with the clinical features of infarct extension. In contrast, the cytochrome c peak value correlated inversely with the myocardial blush grade. Patients with clinical signs of myocardial reperfusion injury had a significantly greater cytochrome c peak value than patients without reperfusion injury (median 1.65 ng/ml, interquartile range 1.20 to 2.20, vs 1.1 ng/ml, interquartile range 0.65 to 1.55; p = 0.04). In conclusion, serum cytochrome c is detectable in the early phase of STEMI treated with pPCI and is associated with clinical signs of impaired myocardial reperfusion. © 2010 Elsevier Inc. All rights reserved.


Titta L.,Italian National Cancer Institute | Titta L.,University of Milan | Trinei M.,Congenia Srl | Stendardo M.,Italian National Cancer Institute | And 12 more authors.
International Journal of Obesity | Year: 2010

Objective:To analyze the effect of the juice obtained from two varieties of sweet orange (Citrus sinensis L. Osbeck), Moro (a blood orange) and Navelina (a blond orange), on fat accumulation in mice fed a standard or a high-fat diet (HFD).Methods:Obesity was induced in male C57/Bl6 mice by feeding a HFD. Moro and Navelina juices were provided instead of water. The effect of an anthocyanin-enriched extract from Moro oranges or purified cyanidin-3-glucoside (C3G) was also analyzed. Body weight and food intake were measured regularly over a 12-week period. The adipose pads were weighted and analyzed histologically; total RNA was also isolated for microarray analysis.Results: Dietary supplementation of Moro juice, but not Navelina juice significantly reduced body weight gain and fat accumulation regardless of the increased energy intake because of sugar content. Furthermore, mice drinking Moro juice were resistant to HFD-induced obesity with no alterations in food intake. Only the anthocyanin extract, but not the purified C3G, slightly affected fat accumulation. High-throughput gene expression analysis of fat tissues confirmed that Moro juice could entirely rescue the high fat-induced transcriptional reprogramming.Conclusion:Moro juice anti-obesity effect on fat accumulation cannot be explained only by its anthocyanin content. Our findings suggest that multiple components present in the Moro orange juice might act synergistically to inhibit fat accumulation. © 2010 Macmillan Publishers Limited All rights reserved.


Grant
Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2007-2.4.3-3 | Award Amount: 3.16M | Year: 2008

Type 2 diabets and obesity are related conditions representing major components of the metabolic syndrome and one of the most challenging health problems of this century, also because of their growing impact in childhood. Different studies have identified PPAR-gamma coactivator-1 (PGC-1alpha) as a relevant type 2 diabetes susceptibility gene playing an important role in human obesity as well. Subsequent investigations led to the discovery that p160MBP (MybBindingProtein) serves as a PGC-1alpha inhibitor. More recently, we showed that p160MBP is controlled by the Prep1 gene. Prep1 hypomorphic mice feature increase sensitivity to insulin due to raised PGC-1 alpha and decreased p160MBP levels. These mice also exhibit decreased fat body mass. Indeed, we also identified Prep1 in genetic screenings in C. Elegans and mouse ,as a major gene involved in energy homeostasis and obesity. Importantly, we have preliminary data showing Prep1 overexpression in euglycemic first-degree relatives of type 2 diabetics, which are at very high risk of diabetes. This project aims at understanding how Prep1 gene controls insulin sensitivity and determines adipogenesis, obesity and type 2 diabetes in humans. We will: 1: elucidate the molecular basis of Prep1 role in insulin sensitivity and adipogenesis through in vitro and animal model studies; 2: assess the significance of Prep1 function to insulin sensitivity in humans and the role of this gene in type 2 diabetes and its subphenotypes and in other components of the metabolic syndrome; 3: identify Prep1 target genes and establish their potential as targets for novel strategies to treat type 2 diabetes and metabolic syndrome. To achieve these objectives we have built a multidisciplinary network and gathered experts in the Prep1/p160MBP signaling, type 2 diabetes and obesity molecular biology and genetics, human and mouse genetics and high throughput analysis of gene expression and identification of target genes.


Acrylamido derivatives useful as therapeutic agents, particularly for the prevention and/or treatment of diseases and conditions associated with the activity of the mitochondrial permeability transition pore (MPTP), such as the diseases characterized by ischemia/reperfusion, oxidative or degenerative tissue damage, are herein described. These compounds belong to the structural formula (I)


Acrylamido derivatives useful as therapeutic agents, particularly for the prevention and/or treatment of diseases and conditions associated with the activity of the mitochondrial permeability transition pore (MPTP), such as the diseases characterized by ischemia/reperfusion, oxidative or degenerative tissue damage, are herein described. These compounds belong to the structural formula (I) wherein R, R, R, W and a are as defined in the specification. The invention also relates to the preparation of these compounds, as well as to pharmaceutical compositions comprising them.

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