PDF(Pubmed)
Abstract：
UNASSIGNED: Oxidative stress is recognized as a major driver of non-alcoholic steatohepatitis (NASH) progression. The transcription factor NRF2 and its negative regulator KEAP1 are master regulators of redox, metabolic and protein homeostasis, as well as detoxification, and thus appear to be attractive targets for the treatment of NASH.
UNASSIGNED: Molecular modeling and X-ray crystallography were used to design S217879 - a small molecule that could disrupt the KEAP1-NRF2 interaction. S217879 was highly characterized using various molecular and cellular assays. It was then evaluated in two different NASH-relevant preclinical models, namely the methionine and choline-deficient diet (MCDD) and diet-induced obesity NASH (DIO NASH) models.
UNASSIGNED: Molecular and cell-based assays confirmed that S217879 is a highly potent and selective NRF2 activator with marked anti-inflammatory properties, as shown in primary human peripheral blood mononuclear cells. In MCDD mice, S217879 treatment for 2 weeks led to a dose-dependent reduction in NAFLD activity score while significantly increasing liver Nqo1 mRNA levels, a specific NRF2 target engagement biomarker. In DIO NASH mice, S217879 treatment resulted in a significant improvement of established liver injury, with a clear reduction in both NAS and liver fibrosis. αSMA and Col1A1 staining, as well as quantification of liver hydroxyproline levels, confirmed the reduction in liver fibrosis in response to S217879. RNA-sequencing analyses revealed major alterations in the liver transcriptome in response to S217879, with activation of NRF2-dependent gene transcription and marked inhibition of key signaling pathways that drive disease progression.
UNASSIGNED: These results highlight the potential of selective disruption of the NRF2-KEAP1 interaction for the treatment of NASH and liver fibrosis.
UNASSIGNED: We report the discovery of S217879 - a potent and selective NRF2 activator with good pharmacokinetic properties. By disrupting the KEAP1-NRF2 interaction, S217879 triggers the upregulation of the antioxidant response and the coordinated regulation of a wide spectrum of genes involved in NASH disease progression, leading ultimately to the reduction of both NASH and liver fibrosis progression in mice.
UNASSIGNED: Molecular modeling and X-ray crystallography were used to design S217879 - a small molecule that could disrupt the KEAP1-NRF2 interaction. S217879 was highly characterized using various molecular and cellular assays. It was then evaluated in two different NASH-relevant preclinical models, namely the methionine and choline-deficient diet (MCDD) and diet-induced obesity NASH (DIO NASH) models.
UNASSIGNED: Molecular and cell-based assays confirmed that S217879 is a highly potent and selective NRF2 activator with marked anti-inflammatory properties, as shown in primary human peripheral blood mononuclear cells. In MCDD mice, S217879 treatment for 2 weeks led to a dose-dependent reduction in NAFLD activity score while significantly increasing liver Nqo1 mRNA levels, a specific NRF2 target engagement biomarker. In DIO NASH mice, S217879 treatment resulted in a significant improvement of established liver injury, with a clear reduction in both NAS and liver fibrosis. αSMA and Col1A1 staining, as well as quantification of liver hydroxyproline levels, confirmed the reduction in liver fibrosis in response to S217879. RNA-sequencing analyses revealed major alterations in the liver transcriptome in response to S217879, with activation of NRF2-dependent gene transcription and marked inhibition of key signaling pathways that drive disease progression.
UNASSIGNED: These results highlight the potential of selective disruption of the NRF2-KEAP1 interaction for the treatment of NASH and liver fibrosis.
UNASSIGNED: We report the discovery of S217879 - a potent and selective NRF2 activator with good pharmacokinetic properties. By disrupting the KEAP1-NRF2 interaction, S217879 triggers the upregulation of the antioxidant response and the coordinated regulation of a wide spectrum of genes involved in NASH disease progression, leading ultimately to the reduction of both NASH and liver fibrosis progression in mice.
摘要：
未经证实：氧化应激被认为是非酒精性脂肪性肝炎（NASH）进展的主要驱动因素。转录因子NRF2及其负调节因子KEAP1是氧化还原的主调节因子,代谢和蛋白质稳态，以及排毒，因此似乎是治疗NASH的有吸引力的靶标。
UNASSIGNED：分子建模和X射线晶体学用于设计S217879-一种可以破坏KEAP1-NRF2相互作用的小分子。使用各种分子和细胞测定高度表征S217879。然后在两个不同的NASH相关临床前模型中进行评估，即蛋氨酸和胆碱缺乏饮食（MCDD）和饮食诱导的肥胖NASH（DIONASH）模型。
UNASSIGNED：基于分子和细胞的检测证实S217879是一种高效和选择性的NRF2激活剂，具有明显的抗炎特性，如原代人外周血单核细胞所示。在MCDD小鼠中,S217879治疗2周导致NAFLD活性评分的剂量依赖性降低，同时显着增加肝脏Nqo1mRNA水平，一种特定的NRF2靶参与生物标志物。在DIONASH小鼠中，S217879治疗导致已建立的肝损伤的显着改善，NAS和肝纤维化均明显减少。αSMA和Col1A1染色，以及肝脏羟脯氨酸水平的定量，证实了响应S217879的肝纤维化的减少。RNA测序分析揭示了响应S217879的肝脏转录组中的主要变化，NRF2依赖性基因转录的激活和驱动疾病进展的关键信号通路的显著抑制。
UNASSIGNED：这些结果突出了NRF2-KEAP1相互作用选择性破坏治疗NASH和肝纤维化的潜力。
UNASSIGNED：我们报告了S217879的发现——一种具有良好药代动力学特性的有效和选择性的NRF2激活剂。通过破坏KEAP1-NRF2相互作用，S217879触发抗氧化反应的上调和涉及NASH疾病进展的广谱基因的协调调节，最终导致小鼠NASH和肝纤维化进展的减少。
UNASSIGNED：分子建模和X射线晶体学用于设计S217879-一种可以破坏KEAP1-NRF2相互作用的小分子。使用各种分子和细胞测定高度表征S217879。然后在两个不同的NASH相关临床前模型中进行评估，即蛋氨酸和胆碱缺乏饮食（MCDD）和饮食诱导的肥胖NASH（DIONASH）模型。
UNASSIGNED：基于分子和细胞的检测证实S217879是一种高效和选择性的NRF2激活剂，具有明显的抗炎特性，如原代人外周血单核细胞所示。在MCDD小鼠中,S217879治疗2周导致NAFLD活性评分的剂量依赖性降低，同时显着增加肝脏Nqo1mRNA水平，一种特定的NRF2靶参与生物标志物。在DIONASH小鼠中，S217879治疗导致已建立的肝损伤的显着改善，NAS和肝纤维化均明显减少。αSMA和Col1A1染色，以及肝脏羟脯氨酸水平的定量，证实了响应S217879的肝纤维化的减少。RNA测序分析揭示了响应S217879的肝脏转录组中的主要变化，NRF2依赖性基因转录的激活和驱动疾病进展的关键信号通路的显著抑制。
UNASSIGNED：这些结果突出了NRF2-KEAP1相互作用选择性破坏治疗NASH和肝纤维化的潜力。
UNASSIGNED：我们报告了S217879的发现——一种具有良好药代动力学特性的有效和选择性的NRF2激活剂。通过破坏KEAP1-NRF2相互作用，S217879触发抗氧化反应的上调和涉及NASH疾病进展的广谱基因的协调调节，最终导致小鼠NASH和肝纤维化进展的减少。
