Structure-Activity Relationship and Biological Investigation of a REV-ERBα-Selective Agonist SR-29065 (34) for Autoimmune Disorders.
Structure-Activity Relationship and Biological Investigation of a REV-ERBα-Selective Agonist SR-29065 (34) for Autoimmune Disorders.
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REV-ERBα-选择性激动剂 SR-29065 (34) 治疗自身免疫性疾病的结构-活性关系和生物学研究。
DOI：
10.1021/acs.jmedchem.3c01413
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发表时间：
2023
影响因子：
7.3
通讯作者：
Kamenecka,TheodoreM
中科院分区：
文献类型：
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作者：
He,Yuanjun;Zhu,Di;Greenman,Kevin;Ruiz,Claudia;Shang,Jinsai;Lu,Qun;Kojetin,DouglasJ;Drakas,Robert;Cameron,MichaelD;Lizarzaburu,Mike;Solt,LauraA;Kamenecka,TheodoreM
自身免疫性疾病影响着5000万美国人，其中主要是女性，被认为是65岁以上女性死亡的十大主要原因之一。全基因组关联研究将TH17细胞中优先表达的基因与几种人类自身免疫性疾病联系起来，突显了TH17细胞的核心作用。我们和其他人已经报道，核受体REV-ERB、α和β是TH17细胞发育和致病性的细胞内源性抑制因子，因此可能成为干预的治疗靶点。在这里，我们描述了一种新型的REV-ERBα选择性支架的详细的合成孔径雷达研究。配体的代谢稳定性被优化，允许在带有配体(34)的多发性硬化症(EAE)小鼠模型中活体询问受体。中枢神经系统中T细胞和关键的REV-ERB靶基因的频率和数量的减少是体内靶参与的一种衡量标准。
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 forin vivointerrogation 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 engagementin vivo.