Development of RORgt Immunomodulators Targeting the TH17 Axis in IBD

描述：Th17细胞是辅助性T细胞的一种，最近被确认为几种人类炎症性疾病状态的免疫病理的关键介质，包括炎症性肠病(IBD)。孤儿核受体ROR？T已被证明是Th17细胞分化的主控者。RoR？t基因敲除动物对几种自身免疫性疾病具有高度抵抗力。在人体内，与其他器官相比，肠道中Th17细胞的比例最高。与IBD相关的是，与野生型相比，与野生型相比，在ROR？T缺失T细胞的动物的肠道固有层中发现Th17细胞的数量显著减少。ROR？T转录活性的拮抗会导致阻止CD4+T细胞向Th17细胞分化。因此，ROR？T拮抗剂可以减少炎症部位的Th17细胞数量。Th17细胞分泌大量IL-17A、IL-17F、IL-22、TNF-？和其他炎性细胞因子。ROR？T对这些细胞因子的产生很重要，已有研究表明，ROR？T拮抗剂可减少已存在的Th17细胞分泌这些细胞因子。因此，ROR？T的小分子拮抗剂可能通过减少Th17细胞群和IL-17A/F的产生而有效地调节IBD的发病。据报道，一些小分子工具化合物可以减轻动物模型中的自身免疫性疾病，但这些化合物都没有足够的类药物性质，可以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，我们对从我们的多种虚拟化合物库(业内最大的)获得的2200万种化合物进行了电子筛选。随后，1000多种商业上可用的类药物化合物在基于细胞的荧光素酶报告分析中被测试对ROR？T介导的转录的拮抗作用。进一步评估了有效的HITS对密切相关核受体的选择性。部分化合物具有抑制人Th17细胞体外分化的功能。基于初步数据的成功，我们提出以下目标：(1)利用我们专有的BindingSIGHTs药物设计平台优化新型ROR？T拮抗剂的药理性质，以指导复杂的药物化学；(2)测定ROR？T拮抗剂对人Th17、Th1、Th2和Treg细胞的体外T细胞功能活性；(3)评价ROR？T拮抗剂在IBD动物模型中的治疗效果。总之，这些研究将为高度先进和新颖的类药物化学物质提供适当的药理学特征，以确定我们方法的可行性。这最终将使后续的IND研究和临床试验成为可能。

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.