Structure-Activity Relationship and Biological Investigation of a REV-ERBα-Selective Agonist SR-29065 ( 34 ) for Autoimmune Disorders.
Yuanjun HeDi ZhuKevin GreenmanClaudia RuizJinsai ShangQun LuDouglas J KojetinRobert DrakasMichael D CameronMike LizarzaburuLaura A SoltTheodore M KameneckaPublished in: Journal of medicinal chemistry (2023)
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-ERBα and β 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-ERBα-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 .
Keyphrases
- multiple sclerosis
- induced apoptosis
- mouse model
- single cell
- cell cycle arrest
- polycystic ovary syndrome
- genome wide association
- structure activity relationship
- genome wide
- endothelial cells
- randomized controlled trial
- pregnancy outcomes
- endoplasmic reticulum stress
- metabolic syndrome
- oxidative stress
- blood brain barrier
- stem cells
- type diabetes
- gene expression
- cell death
- bone marrow
- mesenchymal stem cells
- white matter
- dna methylation
- cervical cancer screening
- insulin resistance
- bioinformatics analysis
- candida albicans
- drug induced
- pluripotent stem cells