Harnessing the synergy between Conformetrix technology and crystallography to expedite identification of novel, selective a4b7 integrin inhibitors for the treatment of IBD

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"The objective for this project is to deliver an oral, small molecule anti-inflammatory agent for the treatment of mild-severe, inflammatory bowel disease (IBD). IBD is a collection of idiopathic diseases caused by a dysregulated immune response to host intestinal microflora. The most common sub-types are ulcerative colitis (a continuous band of inflammation throughout the colon) and Crohn's disease (transmural, ""skip lesions"" affecting any segment of the gastrointestinal tract). IBD patients are stratified as mild, moderate or severe. The current standard treatment for mild patients is aminosalicylate progressing to corticosteroids and then immunosuppressants as disease severity increases. Treatment for mild-moderate patients sees mixed response and is associated with significant side-effects. Moderate/severe patients that do not respond to immunosuppressants are progressed on to biological therapies which have revolutionised the treatment of moderate/severe disease. Unfortunately, a significant proportion of patients do not respond to biological therapies often due to the production of neutralising antibodies. Gastroenterologists have identified a clear need to develop non-biological agents that effectively maintain remission in moderate/severe patients. This need also extends to mild-moderate patients where cost effective, oral, non-biological, anti-inflammatory treatments with improved efficacy and side effects could prevent disease progression.C4X Discovery will use its proprietary Conformetrix technology which has been previously been used to rapidly identify novel chemical scaffolds from known ligands, by elucidating their 3D shape(s) in solution. The technology will be used synergistically with protein crystallography to compare free and bound ligand 3D-shapes to pin-point the exact areas of the molecules that will need optimising leading to the identification of potent anti-inflammatory compounds.An effective, safe, oral small molecule therapy for IBD could meet the healthcare need across IBD patient severities and help reduce the significant economic burden caused by the disease. There are currently over 300,000 patients in the UK with IBD and prevalence increasing. The NHS economic cost of IBD was £720 million in 2006\. An effective oral anti-inflammatory agent will lower the healthcare burden by reduced hospitalisation of patients, lower Cost of Goods compared to biologics, and no necessity for hospital visits for administration, thereby increasing patient access to a life-changing therapy. The positive impact at a patient and community level would be a pain free, convenient, discreet medication reducing social stigma."