Project: NOVEL THERAPEUTIC APPROACHES TO COMBAT OBESITY PANDEMIC AND ITS SEQUELS
The GOAL of the project is to develop small molecule negative modulators of the G protein coupled receptor (GPCR) GPR17 to control inappropriate food intake, obesity and visceral adiposity, which are major risk factors for the onset of type 2 diabetes and of cardiovascular disease._x000D_BACKGROUND_x000D_The prevalence of obesity has grown at an alarming rate, reaching pandemic proportions. Obesity rates in Europe have been rising and are now a serious public health concern, even though at a range of 7.6-24.7% they are much lower than those in the USA which stand at around 27% (European Health Interview Survey, Eurostat; http://epp.eurostat.ec.europa.eu/statistics_explained/index.php/Overweight_and_obesity_-_BMI_statistics; FIGURE 1 Annex). Overweight leads to an increased number of patients affected by the co-morbidities of obesity, such as cardiovascular disease, type 2 diabetes, respiratory disorders, and cancer (Wang et al., 2011; Farag et al., 2012). Considering the staggering cost and serious challenges to public health associated with this condition, the identification of small molecules that can effectively and safely target new biochemical pathways for obesity therapy is receiving increased attention._x000D_GPR17 has been recently identified as a druggable target, expressed on Agouti-related peptide (AgRP) neurons, which are known to regulate feeding behavior and energy metabolism (Ren et al, 2012; FIGURE 2, Annex). This finding leads to a new therapeutic strategy trying to modulate GPR17 on the AgRP neurons. GPR17 is part of the known FoxO1 pathway, central in feeding regulation, for which earlier targeting strategies have had little success._x000D_GPR17 was originally identified as an orphan receptor highly expressed in the CNS and later shown to be activated by two different classes of ligands, uracil nucleotides (UDP-glucose and UDP) and cysteinyl leukotrienes (CysLTs, like LTD4 and LTE4) (Ciana et al., 2006), unveiling an intriguing pharmacology for this dualistic receptor._x000D_Hypothalamic AgRP neurons are functionally important in feeding behavior and energy homeostasis. As a matter of fact their acute ablation in adult mice causes cessation of feeding and results in starvation. The key anorexigenic hormones insulin and leptin, inhibit these neurons, raising their activation threshold. As a transcription factor, FoxO1 integrates both insulin and leptin signaling. FoxO1 knock-outs in mouse AgRP neurons show improved glucose homeostasis, increased insulin/leptin sensitivity. Those mice eat less and are lean (Ren et al. 2012). Apparently, transcription factors are non-druggable, turning the search for small molecule inhibitors of FoxO1 into a huge challenge. _x000D_The expression of GPR17 is regulated by FoxO1. Therefore GPR17 represents a very attractive and innovative target to address inappropriate food intake (FIGURE 3 Annex) and weight management as well as obesity-associated comorbidities._x000D_GPR17 belongs to the large family of GPCRs, which is considered to be the most druggable target class. In addition, GPR17 is a highly innovative molecular target, which was only recently recognized as a key node in the AgRP-FoxO1 pathway, which regulates food intake. This pathway and its molecular targets has been of high interest, but so far has not offered a strategy for pharmaceutical intervention. Having GPR17 identified as a novel player in FoxO1 signaling now provides a druggable target with high potential impact for the development of innovative therapeutics._x000D_Molecules that inhibit the activity of the FoxO1 pathway via GPR17 are expected to impact the development of treatments for different conditions, ranging from visceral adiposity to obesity and possibly also on type-2 diabetes, which are amongst the greatest public health challenges of the 21st century._x000D_CONSORTIUM_x000D_Axxam is a science-driven biotechnology company with a team of almost 50 qualified personnel. It is based in the Z-cube bioincubator, near Milan. The company is recognized as a world leader in assay development, high throughput screening (HTS) and compound profiling and offers early stage discovery research services for the life science. Moreover it also endows in proprietary focused drug discovery projects. The company has developed innovative technologies to improve assay performance (i.e.: Photina®, chAMPion) in HTS._x000D_The Lead Discovery Center GmbH (LDC) was established by the technology transfer organization Max Planck Innovation, to capitalize on the potential of excellent basic research for the discovery of new therapies. With a team of more than 50 scientists, drug discovery experts, pharmacologists and project managers, LDC offers drug discovery support according to the highest industry standards with an emphasis on the hit and lead optimization phases. At LDC all core competencies and expertise required for small molecule drug discovery are established in a fully integrated fashion and supplemented by a strong collaboration network in academia and industry.
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Acronym
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Hypo Greedy
(Reference Number: 8183)
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Duration
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01/12/2013 - 30/11/2016
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Project Topic
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THE ESCALATING GLOBAL EPIDEMIC OF OBESITY IS NOW REWORDED AS AN HEALTH AND SOCIOECONOMIC CHALLENGE FOR ITS LINK TO WIDELY OCCURRING LIFE THREATENING DISEASES. THE PROJECT TARGETS AN INNOVATIVE VENUE OF INTERVENTION FOR ENERGY HOMEOSTASIS REGULATION BY NEGATIVE MODULATORS OF THE DRUGGABLE GPR17.
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Network
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Eurostars
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Call
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Eurostars Cut-Off 10
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Project partner
