Sphingosine Kinase Inhibitors as Anti-IBD Agents

鞘氨醇激酶抑制剂作为抗 IBD 药物

• 批准号: 7278825
• 负责人: LYNN W MAINES
• 金额: $ 87.46万
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7278825
• 关键词: Acute; Acute Toxicity Tests; Address; Animals; Azoxymethane; Canis familiaris; Cell Differentiation process; Clinical Treatment; Clinical Trials; Colon; Colon Carcinoma; Colonic Neoplasms; Condition; Crohn' s disease; Cultured Cells; Cyclic GMP; Data; Development; Drug Formulations; Epithelial Cells; Event; Genus Cola; Goals; Human; Inflammation; Inflammation Process; Inflammatory; Inflammatory Bowel Diseases; Interleukin-10; Investigational New Drug Application; Knock-out; Knockout Mice; Laboratory Procedures; Lead; Lipids; Mediating; Mediator of activation protein; Metabolism; Methods; Modeling; Molecular Target; Mus; Neutrophil Activation; Oral; Oral Administration; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Procedures; Protocols documentation; Rattus; Research; Role; Safety; Schedule; Signal Pathway; Sphingolipids; Sphingosine; TNF gene; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Toxicology; Treatment Protocols; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Ulcerative Colitis; United States Food and Drug Administration; biological adaptation to stress; colon carcinogenesis; cytokine; human TNF protein; in vivo; in vivo Model; inhibitor/antagonist; innovation; kinase inhibitor; mast cell; novel; novel therapeutics; programs; research clinical testing; research study; response; sphingosine 1-phosphate; sphingosine kinase

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）：该项目的目标是开发可有效作为治疗剂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 视为创新分子靶点，用于开发治疗炎症性肠病 (IBD) 的新药。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，并且已知可介导促炎细胞因子肿瘤坏死因子-a (TNFa) 的作用，而肿瘤坏死因子-a (TNFa) 在 IBD 中至关重要。由于 SK 在调节炎症方面的关键作用，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，并且口服这些化合物可以减轻溃疡性结肠炎 DSS 模型中 IBD 的发展，并且对小鼠没有毒性。这些研究首次提供了原理证明，证明 SK 抑制剂可能有效治疗 IBD。该项目的第二阶段将解决以下具体目标： 评估口服 ABC294640 和 ABC747080 在克罗恩病 TNBS 模型和 IL-10 敲除小鼠中的抗 IBD 活性；从药效学角度优化 ABC294640 和 ABC747080 的口服给药方案；确定 ABC294640 和 ABC747080 在炎症驱动的结肠癌模型中的功效；使用单一最佳 SK 抑制剂完成 cGMP 合成和制剂以及 IND 指导的毒理学研究。所提出的研究代表了一种将新型 SK 抑制剂纳入 IBD 治疗临床试验的重点方法。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。