Structure–Activity Relationship and Biological Investigation of a REV-ERBα-Selective Agonist SR-29065 (<b>34</b>) 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 TH17 cells has been highlighted by genome-wide association studies (GWAS) linking genes preferentially expressed in TH17 cells to several human autoimmune diseases. We and others have reported that the nuclear receptors REV-ERBα and β are cell-intrinsic repressors of TH17 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.自身免疫性疾病影响5000万美国人，患者以女性为主，且被列为65岁以下女性群体十大主要致死病因之一。全基因组关联研究（GWAS）已证实，优先在辅助性T细胞17（TH17 cells）中表达的基因与多种人类自身免疫性疾病相关，由此凸显了TH17细胞的核心作用。我们与其他研究团队均已报道，核受体REV-ERBα与β是辅助性T细胞17发育与致病能力的细胞内源性阻遏物，因此有望成为干预治疗的靶点。本文详细阐述了一款新型REV-ERBα选择性骨架的构效关系（SAR）研究。研究人员对配体的代谢稳定性进行优化，得以借助化合物34在多发性硬化小鼠模型（实验性自身免疫性脑脊髓炎，EAE）中开展受体的体内探究。中枢神经系统（CNS）中T细胞的频率与数量减少，以及关键REV-ERB靶基因的表达水平下调，均可作为体内靶点结合效应的评价指标。