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. ? ? ?
