Sphingosine Kinase Inhibitors as Anti-IBD Agents

描述(由申请人提供)：该计划的目标是开发新型的人神经鞘氨酸激酶(SK)抑制剂，作为有效的治疗剂。由于SK在鞘磷脂代谢中的关键作用，我们一直将SK作为开发治疗炎症性肠病(IBDS)新药的创新分子靶点。鞘磷脂被认为是应激反应、细胞分化和增殖的关键介质，并被认为是介导炎性细胞因子肿瘤坏死因子(TNFa)的作用，而肿瘤坏死因子在IBD中起着核心作用。由于SK在调节炎症中的关键作用，我们正在开发SK抑制剂，将其用作治疗IBD的药物。在该计划的第一阶段，我们证明了我们的SK抑制剂可以阻断炎症细胞因子诱导的信号通路，口服这些化合物可以缓解DSS溃疡性结肠炎模型中IBD的发展，对小鼠没有毒性。这些研究首次证明SK抑制剂在IBD的治疗中可能是有效的。该项目的第二阶段将致力于以下具体目标：评估口服ABC294640和ABC747080在克罗恩病TNBS模型和IL-10基因敲除小鼠中的抗IBD活性；药效学优化ABC294640和ABC747080的口服给药时间表；确定ABC294640和ABC747080在炎症驱动的结肠癌模型中的疗效；以及完成单一最佳SK抑制剂的cGMP合成、制剂和工业毒理学研究。建议的研究代表了一种有重点的方法，将一种新的SK抑制剂转移到治疗IBD的临床试验中。在这些实验完成后，我们将准备开始对单一的最佳候选药物进行临床测试。

DESCRIPTION (provided by applicant): The goal of this program is to develop novel inhibitors of human sphingosine kinase (SK) that are effective as therapeutic agents. Because of its critical role in sphingolipid metabolism, we have focused on SK as an innovative molecular target for the development of new drugs for the treatment of Inflammatory Bowel Diseases (IBDs). Sphingolipids are being increasingly recognized as key mediators of stress responses, cell differentiation and proliferation, and are known to mediate the effects of the pro-inflammatory cytokine tumor necrosis factor-a (TNFa) that is of central importance in IBDs. Because of this pivotal role of SK in regulating inflammation, we are developing SK inhibitors to be used as drugs to treat IBDs. In Phase I of this program, we demonstrated that our SK inhibitors block signaling pathways induced by inflammatory cytokines, and that oral administration of these compounds alleviates the development of IBD in the DSS model of ulcerative colitis, without toxicity to the mice. These studies provide the first proof-of-principle demonstration that SK inhibitors are likely to be effective in the treatment of IBD. The following Specific Aims will be addressed in Phase II of this project: To evaluate the anti-IBD activity of orally-delivered ABC294640 and ABC747080 in the TNBS-model of Crohn's Disease and in IL-10 knock-out mice; To pharmacodynamically optimize the schedule for oral delivery of ABC294640 and ABC747080; To determine the efficacies of ABC294640 and ABC747080 in the inflammation-driven model of colon carcinogenesis; and To complete cGMP synthesis and formulation and IND-directed toxicology studies with the single best SK inhibitor. The studies proposed represent a focused approach for moving a novel inhibitor of SK into clinical trials for the treatment of IBDs. Upon the completion of these experiments, we will be ready to begin clinical testing of the single best drug candidate.