PDF(Pubmed)
Abstract：
Functional variants of the gene for the cytokine macrophage migration inhibitory factor (MIF) are defined by a 4-nucleotide promoter microsatellite (-794 CATT5-8, rs5844572) and confer risk for autoimmune, infectious, and oncologic diseases. We describe herein the discovery of a prototypic, small molecule inhibitor of MIF transcription with selectivity for high microsatellite repeat number and correspondingly high gene expression. Utilizing a high-throughput luminescent proximity screen, we identify 1-carbomethoxy-5-formyl-4,6,8-trihydroxyphenazine (CMFT) to inhibit the functional interaction between the transcription factor ICBP90 (namely, UHRF1) and the MIF -794 CATT5-8 promoter microsatellite. CMFT inhibits MIF mRNA expression in a -794 CATT5-8 length-dependent manner with an IC50 of 470 nM, and preferentially reduces ICBP90-dependent MIF mRNA and protein expression in high-genotypic versus low-genotypic MIF-expressing macrophages. RNA expression analysis also showed CMFT to downregulate MIF-dependent, inflammatory gene expression with little evidence of off-target metabolic toxicity. These findings provide proof-of-concept for advancing the pharmacogenomic development of precision-based MIF inhibitors for diverse autoimmune and inflammatory conditions.
摘要：
细胞因子巨噬细胞迁移抑制因子（MIF）基因的功能变体由4个核苷酸的启动子微卫星（-794CATT5-8，rs5844572）定义，并赋予自身免疫性风险，传染性,和肿瘤疾病。我们在这里描述了原型的发现，MIF转录的小分子抑制剂，具有高微卫星重复数的选择性和相应的高基因表达。利用高通量发光接近屏，我们鉴定了1-碳甲氧基-5-甲酰基-4,6,8-三羟基吩嗪（CMFT）以抑制转录因子ICBP90（也称为UHRF1）和MIF-794CATT5-8启动子微卫星之间的功能相互作用。CMFT以-794CATT5-8长度依赖性方式抑制MIFmRNA表达，IC50为470nM，并优先降低高基因型与低基因型MIF表达巨噬细胞中ICBP90依赖性MIFmRNA和蛋白质的表达。RNA表达分析还显示CMFT下调MIF依赖性，炎症基因表达，很少有脱靶代谢毒性的证据。这些发现为推进基于精确的MIF抑制剂用于多种自身免疫和炎性病症的药物基因组开发提供了概念验证。
