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

“该项目的目标是提供一种口服小分子抗炎剂，用于治疗轻度-重度炎症性肠病（IBD）。IBD是由对宿主肠道菌群的免疫应答失调引起的特发性疾病的集合。最常见的亚型是溃疡性结肠炎（整个结肠的连续炎症带）和克罗恩病（影响胃肠道任何部分的透壁性“跳跃性病变”）。IBD患者分为轻度、中度或重度。目前轻度患者的标准治疗是氨基水杨酸，随着疾病严重程度的增加，逐渐发展为皮质类固醇，然后是免疫抑制剂。轻中度患者的治疗反应不一，并伴有显著的副作用。对免疫抑制剂无反应的中度/重度患者进展为生物疗法，这彻底改变了中度/重度疾病的治疗。不幸的是，很大一部分患者对生物疗法没有反应，这通常是由于中和抗体的产生。胃肠病学家已经明确需要开发非生物制剂，以有效维持中度/重度患者的缓解。这一需求也扩展到轻中度患者，在这些患者中，具有成本效益的口服非生物抗炎治疗方法可以改善疗效和副作用，从而防止疾病进展。C4 X Discovery将使用其专有的Confortron技术，该技术以前曾用于从已知配体中快速识别新型化学支架，通过阐明其在溶液中的3D形状。该技术将与蛋白质晶体学协同使用，比较游离和结合配体的3D形状，以确定需要优化的分子的确切区域，从而识别有效的抗炎化合物。有效，安全的IBD口服小分子治疗可以满足IBD患者严重程度的医疗保健需求，并有助于减轻疾病造成的重大经济负担。目前，英国有超过30万名IBD患者，患病率不断上升。2006年，IBD的NHS经济成本为7.2亿英镑。一种有效的口服抗炎药将通过减少患者住院、与生物制剂相比更低的商品成本以及无需医院就诊来降低医疗负担，从而增加患者获得改变生活的治疗的机会。在患者和社区层面的积极影响将是一种无痛，方便，谨慎的药物，减少社会耻辱。"

"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."