Sphingosine Kinase Inhibitors as Anti-IBD Agents

描述（由申请人提供）：该项目的目标是开发有效的治疗药物的新型人鞘氨醇激酶（SK）抑制剂。由于其在鞘脂代谢中的关键作用，我们将SK作为开发治疗炎症性肠病（IBDs）新药的创新分子靶点。鞘脂越来越被认为是应激反应、细胞分化和增殖的关键介质，并且已知可以介导促炎细胞因子肿瘤坏死因子-a （TNFa）的作用，TNFa在ibd中起着至关重要的作用。由于SK在调节炎症中的关键作用，我们正在开发SK抑制剂作为治疗ibd的药物。在该项目的I期研究中，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，并且这些化合物的口服可以减轻溃疡性结肠炎DSS模型中IBD的发展，对小鼠没有毒性。这些研究提供了SK抑制剂可能有效治疗IBD的第一个原理证明。该项目的II期研究将实现以下具体目标：评估口服给药ABC294640和ABC747080在克罗恩病tnbs模型和IL-10敲除小鼠中的抗ibd活性；对ABC294640和ABC747080口服给药时间进行药效学优化；测定ABC294640和ABC747080在炎症驱动结肠癌模型中的作用；并完成cGMP的合成和配方以及单一最佳SK抑制剂的ind指导毒理学研究。提出的研究代表了将一种新的SK抑制剂转移到治疗IBDs的临床试验中的重点方法。在完成这些实验后，我们将准备开始对单一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.