A Transporter Platform Technology For Discovery of Drugs to Treat Autoimmune Disease

Project Summary Abstract ! The longterm goal of Apricity TherapeuticsIncApricityis to target pharmacological transporters in the Solute Carrier superfamilySLCto treat diseases for which there are no available pharmacological therapies or current therapies are inadequateSLCs are emerging drug targets because of their numerous associations in human genetic studies with a wide array of common and rare diseasesAutoimmune diseases including inflammatory bowel diseaseIBDsystemic lupus erythematosusSLErheumatoid arthritis and vitiligo are highly associated with polymorphisms in SLC genessuggesting that SLCs play a major role in the inflammatory and abnormal immune responses that characterize these diseasesThe overall goal of this SBIR Phase I proposal is to develop a platform technology for targeting SLC transporters for the treatment of autoimmune diseases with an initial focus on IBDCrohnandapos s disease and ulcerative colitisIn the United StatesIBD is a common autoimmune disease that affectsmillion peopleThe disease involves an immune response and inflammation in the gastrointestinal tractGenomewide association studies and knockout mice studies have provided evidence that members of several SLC families play a role in the etiology and progression of IBD as well as SLEIn this SBIR Phase I applicationwe propose to develop reagents that can be used to screen for small molecule inhibitors of transporters in one of the SLC familiesTwo aims are proposedIn Aimstable cell lines functionally expressing each of the SLC transporters on the plasma membrane will be established and characterizedIn Aimfluorescence assays for high throughput screening will be developed and usedin up to two of the cell linesto screen a large compound library to discover lead molecules that inhibit uptake of canonical substrates of the transportersFollow up studies will be performed to determine the potency and specificity of the compounds in inhibiting each of the transportersFrom the proposed researchwe expect to discover small molecules with different chemical scaffolds that potently and selectively inhibit these SLC transportersThis innovative project is the first to discover small molecules that target a family of SLC transporters and that can be developed as therapies for autoimmune diseases Narrative Autoimmune disease is a debilitating health problem worldwide as the human immune system becomes hyperactive and wreaks havoc on individualsandaposbodiesUnfortunatelythere is no effective drug treatment for many autoimmune diseases such as inflammatory bowel diseaseThe research outlined here will lead to the discovery of new drugs to treat autoimmune disease