Sphingosine Kinase Inhibitors as Anti-IBD Agents

鞘氨醇激酶抑制剂作为抗 IBD 药物

• 批准号: 7050857
• 负责人: LYNN W MAINES
• 金额: $ 17.66万
• 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: 2005-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7050857
• 关键词: disease /disorder model; drug design /synthesis /production; drug screening /evaluation; enzyme inhibitors; gastrointestinal disorder chemotherapy; gastrointestinal epithelium; gastrointestinal pharmacology; inflammation; inflammatory bowel diseases; laboratory mouse; leukocyte activation /transformation; mast cell; neutrophil; phosphotransferases; sphingosine; tissue /cell culture; tumor necrosis factor alpha; ulcerative colitis

DESCRIPTION (provided by applicant): The long-term 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 apoptosis, stress responses, cell differentiation and proliferation, and are known to mediate the effects of the pro- inflammatory cytokine tumor necrosis factor-alpha (TNFalpha) that is of central importance in IBDs. We hypothesize that sphingosine-1-phosphate (S1P) produced by SK within luminal epithelial cells in response to TNFalpha is critical to the cascade of events that results in the recruitment and activation of neutrophils and mast cells that further escalate the inflammation process in IBDs. Therefore, SK is a key molecular target for the development of new therapeutic agents. In spite of accumulating evidence for a pivotal role of SK in regulating immune function, pharmacological inhibition of SK is an untested means of treating inflammatory diseases, including IBDs. This is largely due to the heretofore lack of pharmacologically useful SK inhibitors. To overcome this problem, we have recently identified novel inhibitors of human SK. These compounds are more potent than any other known SK inhibitor, and do not compete for the ATP binding site of the enzyme. We hypothesize that these SK inhibitors can be used to block the effects of inflammatory cytokines and thereby ameliorate IBD pathologies. To provide proof-of-principle evaluation of the utility of these compounds, the following Specific Aims will be addressed during Phase I of this project: 1). To determine the in vitro effects of SK inhibitors on the actions of the pro-inflammatory cytokine TNFalpha; and 2). To evaluate the therapeutic efficacies of SK inhibitors in a mouse model of ulcerative colitis. Because of our previous work that led to the identification of these compounds and the development of methods for their synthesis, as well as the demonstrated expertise of our Consultant with IBD models, we are currently in a unique position to undertake the proposed studies.

描述（由申请人提供）：该项目的长期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细胞凋亡、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-α（TNF α）的作用。我们假设SK在腔上皮细胞内响应TNF α产生的鞘氨醇-1-磷酸（S1 P）对导致中性粒细胞和肥大细胞募集和激活的级联事件至关重要，这些事件进一步加剧了IBD的炎症过程。因此，SK是开发新治疗剂的关键分子靶标。 尽管有越来越多的证据表明SK在调节免疫功能中具有关键作用，但SK的药理学抑制是治疗炎性疾病（包括IBD）的未经测试的手段。这主要是由于迄今为止缺乏非常有用的SK抑制剂。为了克服这个问题，我们最近发现了新的抑制剂的人SK。这些化合物比任何其他已知的SK抑制剂更有效，不竞争的ATP结合位点的酶。我们假设这些SK抑制剂可用于阻断炎性细胞因子的作用，从而改善IBD病理。为了提供这些化合物效用的原理验证评价，在本项目的第I阶段将解决以下具体目标：1）。确定SK抑制剂对促炎细胞因子TNF α的作用的体外作用;和2）。评价SK抑制剂在小鼠溃疡性结肠炎模型中的治疗效果。 由于我们之前的工作导致了这些化合物的鉴定和合成方法的开发，以及我们的顾问在IBD模型方面的专业知识，我们目前处于独特的位置来进行拟议的研究。