Sphingosine Kinase Inhibitors as Anti-IBD Agents

鞘氨醇激酶抑制剂作为抗 IBD 药物

• 批准号: 7154216
• 负责人: LYNN W MAINES
• 金额: $ 81.98万
• 依托单位: APOGEE BIOTECHNOLOGY CORPORATION
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7154216
• 关键词: Crohn' s disease; cancer prevention; chemoprevention; colon neoplasms; disease /disorder model; drug screening /evaluation; gastrointestinal disorder chemotherapy; gastrointestinal pharmacology; genetically modified animals; guanosine monophosphate; inflammatory bowel diseases; interleukin 10; intestinal mucosa; kinase inhibitor; laboratory mouse; laboratory rat; nonhuman therapy evaluation; sphingolipids; sphingosine; tumor necrosis factor alpha

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.

描述（由申请人提供）：本项目的目标是开发新型的人鞘氨醇激酶（SK）抑制剂，作为治疗药物有效。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（IBD）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，并且已知其介导在IBD中至关重要的促炎细胞因子肿瘤坏死因子-a（TNFa）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，用作治疗IBD的药物。在该项目的第一阶段，我们证明了我们的SK抑制剂阻断了由炎性细胞因子诱导的信号传导途径，并且口服这些化合物可以在溃疡性结肠炎的DSS模型中抑制IBD的发展，而对小鼠没有毒性。这些研究提供了第一个原理证明，即SK抑制剂可能有效治疗IBD。本项目II期研究的具体目的如下：在克罗恩病TNBS模型和IL-10基因敲除小鼠中评价口服给药的ABC 294640和ABC 747080的抗IBD活性;确定ABC 294640和ABC 747080在炎症驱动的结肠癌发生模型中的功效;并使用单一最佳SK抑制剂完成cGMP合成和配制以及IND指导的毒理学研究。提出的研究代表了一种将新型SK抑制剂转移到IBD治疗临床试验中的集中方法。在完成这些实验后，我们将准备开始临床试验的单一最佳候选药物。