Structure-Activity Relationship and Biological Investigation of a REV-ERBα-Selective Agonist SR-29065 (34) for Autoimmune Disorders

Autoimmune diseases affect 50 million Americans, predominantly women, and are thought to be one of the top 10 leading causes of death among women in age groups up to 65 years. A central role for T(H)17 cells has been highlighted by genome-wide association studies (GWAS) linking genes preferentially expressed in T(H)17 cells to several human autoimmune diseases. We and others have reported that the nuclear receptors REV-ERB alpha and beta are cell-intrinsic repressors of T(H)17 cell development and pathogenicity and might therefore be therapeutic targets for intervention. Herein, we describe detailed SAR studies of a novel REV-ERB alpha-selective scaffold. Metabolic stability of the ligands was optimized allowing for in vivo interrogation of the receptor in a mouse model of multiple sclerosis (EAE) with a ligand (34). Reduction in frequency and number of T-cells in the CNS as well as key REV-ERB target genes is a measure of target engagement in vivo.

Automated summary

Autoimmune diseases affect a large number of Americans, especially women. T(H)17 cells play a significant role in these diseases, and nuclear receptors REV-ERB alpha and beta have been identified as potential therapeutic targets for suppressing T(H)17 cell development and pathogenicity. A novel REV-ERB alpha-selective scaffold was studied in a mouse model, demonstrating its efficacy in targeting the receptor.