Project: Novel therapeutic approaches for resolution of inflammation

The GOAL of the ChemExit project is to develop small molecule positive modulators, possibly allosteric, of the G protein coupled receptor (GPCR) ChemR23 to treat a range of human inflammatory and autoimmune disorders._x000D__x000D_BACKGROUND_x000D_Non resolved inflammation is a determinant component of many human chronic diseases which have joined the group of well-recognized "inflammatory diseases". Resolution of inflammation, once considered a passive process, is now recognized as an active process, which takes place locally and is essential for healthy tissues and return to homeostasis._x000D_Considering this new concept it is evident that targeting resolution is not equivalent to classical approaches to inhibit inflammation; pro-resolution programs stimulate and activate endogenous pathways to terminate inflammation and to cure chronic forms of diseases._x000D_Recent results have established novel families of lipid mediators (lipoxins, resolvins and protectins) and some of their cognate receptors which direct resolution of inflammation, providing innovative therapeutic venues for resolution-based pharmacology in the treatment of inflammatory disorders [FIGURE 1]._x000D_A central node and an attractive molecular target in the pro-resolution pathway is represented by ChemR23 [FIGURE 2]. ChemR23 was proposed to act as a pro-inflammatory receptor through the binding of the peptide chemerin. However, in vivo work performed with ChemR23 KO mice has shown a role of ChemR23 in the resolution phase of inflammation. This action is likely to be mediated by Resolvin E1 (RevE1), a lipid mediator that binds ChemR23 with high affinity. RevE1 was demonstrated to stimulate resolution of inflammation in vitro and in animal models. Therefore ChemR23 has been identified as a multifunctional receptor; its activation by different ligands activates different signaling cascades with various biological consequences [FIGURE 3]._x000D_Thus ChemR23 represents a very attractive and innovative target to address resolution of inflammation in a variety of human acute and chronic diseases which have a recognized inflammatory component._x000D_As a GPCR it belongs to one of the most druggable target classes and is highly amenable for pharmaceutical development. Then it represents a highly innovative molecular target being only recently recognized as a resolving receptor. This receptor belongs to a new group of recently recognized multimodal, ligand-biased receptors and also is a key node in a new molecular pathway which regulates the active resolution of inflammation. This pathway and its molecular targets represents a new area of interventions with high potential impact for the development of innovative therapeutics._x000D__x000D_APPLICATIONS_x000D_Molecules that stimulate the activity of the RevE1/ChemR23 pathway are expected to impact in the development of treatments for different inflammatory conditions, ranging from autoimmune diseases (e.g. rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease) over chronic inflammatory diseases (e.g. asthma, atherosclerosis, Alzheimer’s, Parkinson’s disease) to sepsis and cancers._x000D__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 for bioactives identification. _x000D_The Lead Discovery Center GmbH (LDC) was established by the technology transfer organization Max Planck Innovation, as a novel approach to capitalize on the potential of excellent basic research for the discovery of new therapies for diseases with high medical need. With a team of 47 interdisciplinary scientists, drug discovery experts, pharmacologists and seasoned project managers, the LDC offers the full scope of drug discovery support according to the highest industry standards with emphasis on the hit and lead optimization phases. At LDC all core competencies and expertises required for small molecule drug discovery are established in a fully integrated fashion and supplemented by a strong collaboration network in academia and industry._x000D_The group of Silvano Sozzani (ICH - Humanitas Research Institute) has a long lasting tradition in studying the role of GPCRs in inflammation.This group was involved in the identification of chemerin as a bioactive ligand of ChemR23 and in the mapping of ChemR23 expression and function in human inflammatory and autoimmune pathologies. This group has a strong tradition in the use of in vitro and in vivo immune models to assess the contribution of immune cells in acute and chronic inflammatory diseases._x000D_

Acronym ChemExit (Reference Number: 7306)
Duration 01/07/2012 - 30/06/2015
Project Topic Non resolved inflammation is considered a major component of many widely occorring diseases. THE PROJECT TARGETS AN INNOVATIVE VENUE OF INFLAMMATION RESOLUTION BY POSITIVE ALLOSTERIC MODULATORS OF THE RESOLVIN RECEPTOR, CHEMR23, TO DEVELOP NEW THERAPEUTICS FOR THE TREATMENT OF INFLAMMATORY DISEASES.
Network Eurostars
Call Eurostars Cut-Off 8

Project partner

Number Name Role Country
3 Humanitas Mirasole SpA Partner Italy
3 Lead Discovery Center GmbH Partner Germany
3 Axxam SpA Coordinator Italy