NONPEPTIDE ANTAGONISTS OF CCR-7 FOR IMMUNOSUPPRESSION

Multiple sclerosis (MS) is a chronic autoimmune disease that afflicts roughly 300,000 Americans. The disease involves immune-mediated inflammation of the central nervous system (CNS) which leads to paralysis, bowel and bladder incontinence, and blindness. Neuro-inflammation in MS is mediated by inflammatory autoreactive T cells that recognize self-antigens from the CNS and require ontinual re-activated with antigen in secondary lymphoid organs (i.e., lymph nodes). Recently, it has been discovered that the two chemokines (i.e., small chemotactic cytokines), macrophage inflammatory protein (MIP)-3beta and secondary lymphoid organ chemokine (SLC), play a fundamental role in the migration of T cells and antigen-presenting cells (APCs), such as dendritic cells (DC), to secondary lymphoid organs. Expression of these chemokines is constitutive and limited to secondary lymphoid organs, and attracts T cells and mature DC (DC that have processed antigen) that express CC chemokine receptor 7 (CCR7), the G-protein coupled receptor (GPCR) for these two chemokines. Thus, our objective is to develop an orally-active small molecule antagonists of CCR7 that would prevent the migration of pathogenic T cells and DC to lymph nodes, which would be a powerful approach to suppressing T cell activation during the autoimmune process and, in turn, blocking end-stage inflammation. To accomplish this goal, our Specific Aims for this Phase I are (i) to synthesize focused combinatorial small molecule libraries based on lead antagonist compounds to identify high-affinity antagonists (Ki < 50 nM) for CCR7, (ii) to demonstrate that the high-affinity antagonists specifically interact with CCR7 on native-receptor expressing cells and selectively inhibit CCR7-mediated cellular responses (i.e., calcium mobilization and chemotaxis), (iii) to assess stability and toxicity of lead compounds in vitro and in vivo, and (iv) to assess whether lead compounds show in vivo efficacy in rodent models of MS and other autoimmune diseases. Indeed, a favorable out-come of these experiments would support the therapeutic potential of CCR7 antagonists in MS