The National Institute of Health (NIH) and the National Institute of Allergy and Infectious Diseases (NIAID) have awarded Torrey Pines Institute for Molecular Studies (TPIMS) a $3,094,096 grant to identify and characterize novel small molecule RORγ antagonists for the treatment of inflammatory autoimmune diseases. Dr. F. Javier Piedrafita, a cancer cell biologist with expertise in nuclear hormone receptors and protein kinases, and Dr. Adel Nefzi, an organic chemist with expertise in combinatorial chemistry have teamed up as Principal Investigators in this bi-coastal research project at Torrey Pines Institute to discover and optimize novel ligands of RORγ to evaluate in animal models of multiple sclerosis. The team will be supported by other faculty members of TPIMS, Dr. Vipin Kumar, an expert in autoimmune disease and Dr. Maria A Ortiz, an expert in nuclear hormone receptors who was involved in the original cloning of RORγ.
RORγ is a member of the ROR (Retinoic acid-related Orphan Receptor) subfamily of Nuclear Hormone Receptors, one of the largest families of ligand-modulated transcription factors that exist in mammalian cells. RORs have been classified as Orphan Nuclear Receptors for a long time, since no ligand had been known to modulate their transcriptional activity until very recently.
Many nuclear hormone receptors are involved in a variety of human diseases, including cancer, metabolic and immune diseases. RORγt (a thymus-specific isoform of RORγ) and later RORα, have been identified as essential regulators of Th-17 cell differentiation, which is characterized by the production of pro-inflammatory cytokines (including IL-17A, IL-17F, IL-21, and IL-22). Importantly, Th-17 cells have a pathogenic role in several autoimmune and inflammatory diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type I diabetes, and psoriasis. Targeting Th-17 cell differentiation by inhibiting RORγt and/or RORα has thus become an attractive strategy for the potential treatment of inflammatory autoimmune diseases.
The screening of the unique collection of small molecule mixture-based combinatorial libraries at TPIMS led to the discovery of potent and selective inhibitors of RORγ in biochemical and cellular assays. The grant awarded by NIAID will be used by Dr. Piedrafita and Dr. Nefzi to identify novel hits, which will be optimized following structure activity relationship (SAR) and computational-guided medicinal chemistry approach to advance leads for in vivo evaluation in a mouse model of autoimmune disease.