Development of RORgt Immunomodulators Targeting the TH17 Axis in IBD

产品说明：Th 17细胞是T辅助细胞的谱系，其最近被鉴定为包括炎性肠病（IBD）在内的几种人类炎性疾病状态的免疫病理学的关键介质。孤儿核受体T细胞已经被证明是Th 17细胞分化的主控制器。吼？T基因敲除动物对几种自身免疫性疾病具有高度抗性。在体内，与其他器官相比，肠道具有最高比例的Th 17细胞。与IBD相关，在ROR？与野生型相比，T-无效T细胞。ROR转录活性的拮抗作用？t导致阻断CD 4 + T细胞向Th 17细胞谱系的分化。因此，ROR？t拮抗剂减少炎症部位的Th 17细胞群。Th 17细胞分泌大量IL-17 A、IL-17 F、IL-22、TNF-？和其他炎性细胞因子。吼？t是重要的生产这些细胞因子，它已被证明，ROR？T拮抗剂减少这些细胞因子从预先存在的Th 17细胞的分泌。因此，小分子拮抗剂的ROR？通过减少Th 17细胞群和IL-17 A/F的产生，它将有效地调节IBD的发病机制。已经报道了一些小分子工具化合物在动物模型中减弱自身免疫性疾病，但这些化合物都不具有足够的药物样性质，被认为是药物发现计划的可行起点。使用我们专有的ROR？t BindingSIGHTs（正在申请专利）结构导向药物设计平台我们对MANIFOLD虚拟化合物库（业界最大的化合物库）中的2200万种化合物进行了计算机筛选。随后，超过1000个市售的药物样化合物进行了测试，在基于细胞的荧光素酶报告基因测定的ROR？t介导的转录。进一步评价有效命中物对密切相关的核受体的选择性。一些化合物具有抑制人Th 17细胞离体分化的功能活性。基于初步数据的成功，我们提出了以下目标：（1）优化新的ROR的药理学性质？t拮抗剂使用我们专有的BindingSIGHTs药物设计平台，以指导复杂的药物化学;（2）确定ROR的体外T细胞功能活性？t拮抗剂对人Th 17、Th 1、Th 2和Treg细胞的作用;（3）评价ROR？在IBD动物模型中测试拮抗剂。总之，这些研究将提供具有适当药理学特征的高度先进和新型药物样化学物质，以确定我们方法的可行性。这将最终实现后续IND使能研究和临床试验。

DESCRIPTION: Th17 cells are a lineage of T helper cells that have recently been identified as critical mediators of the immunopathology of several human inflammatory disease states, including inflammatory bowel disease (IBD). The orphan nuclear receptor ROR?t has been shown to be the master controller of the differentiation of Th17 cells. ROR?t knockout animals are highly resistant to several autoimmune diseases. In the body the intestine has the highest proportion of Th17 cells compared to other organs. With relevance to IBD, substantially reduced numbers of Th17 cells are found in the intestinal lamina propria of animals with ROR?t-null T-cells, compared to wild-type. Antagonism of the transcriptional activity of ROR?t results in blocking the differentiation of CD4+ T-cells to the Th17 cell lineage. Thus, ROR?t antagonists reduce the Th17 cell population at sites of inflammation. Th17 cells secrete large quantities of IL-17A, IL-17F, IL-22, TNF-? and other inflammatory cytokines. ROR?t is important for production of these cytokines and it has been demonstrated that ROR?t antagonists reduce the secretion of these cytokines from pre-existing Th17 cells. Therefore, small molecule antagonists of ROR?t will be efficacious in modulating the pathogenesis of IBD by reduction of the Th17 cell population and IL-17A/F production. Some small molecule tool compounds have been reported that attenuate autoimmune disease in animal models, but none of these possess sufficient drug-like properties to be considered as viable starting points for drug discovery programs. Using our proprietary ROR?t BindingSIGHTs (patent pending) structure-guided drug design platform we have performed an in silico screen of 22 million compounds obtained from our MANIFOLD virtual compound library (the largest in the industry). Subsequently, more than 1000 commercially available drug-like compounds were tested in cell-based luciferase reporter assays for antagonism of ROR?t-mediated transcription. Potent hits were further evaluated for selectivity against closely related nuclear receptors. Some compounds were functionally active to inhibit the ex vivo differentiation of human Th17 cells. Based on the success of the preliminary data we propose the following aims: (1) optimize the pharmacological properties of novel ROR?t antagonists using our proprietary BindingSIGHTs drug design platform to guide sophisticated medicinal chemistry; (2) determine the ex vivo T-cell functional activity of ROR?t antagonists on human Th17, Th1, Th2 and Treg cells; (3) evaluate the therapeutic efficacy of ROR?t antagonists in animal models of IBD. Together, these studies will provide highly advanced and novel drug-like chemical matter with the appropriate pharmacological profile to establish the feasibility of our approach. This will ultimately enable subsequent IND-enabling studies and clinical trials.