Abstract：
Duchenne muscular dystrophy (DMD) is a fatal muscle-wasting disease caused by the absence of a dystrophin protein. Elevating utrophin, a dystrophin paralogue, offers an alternative therapeutic strategy for treating DMD, irrespective of the mutation type. Herein, we report the design and synthesis of novel quinazoline and quinoline-based small molecules as potent utrophin modulators screened via high throughput In-Cell ELISA in C2C12 cells. Remarkably, lead molecule SG-02, identified from a library of 70 molecules, upregulates utrophin 2.7-fold at 800 nM in a dose-dependent manner, marking the highest upregulation within the nanomolar range. SG-02\'s efficacy was further validated through DMD patient-derived cells, demonstrating a significant 2.3-fold utrophin expression. Mechanistically, SG-02 functions as an AhR antagonist, with excellent binding affinity (Kd = 41.68 nM). SG-02 also enhances myogenesis, as indicated by an increased MyHC expression. ADME evaluation supports SG-02\'s oral bioavailability. Overall, SG-02 holds promise for addressing the global DMD population.
摘要：
杜氏肌营养不良症（DMD）是一种致命的肌肉萎缩疾病，由缺乏肌营养不良蛋白引起。升高的乌罗素,肌营养不良蛋白旁白，提供了治疗DMD的替代治疗策略，无论突变类型。在这里，我们报道了在C2C12细胞中通过高通量细胞内ELISA筛选出的新型喹唑啉和基于喹啉的小分子作为有效的utrophin调节剂的设计和合成。值得注意的是,从70个分子的文库中鉴定出的铅分子SG-02，以剂量依赖的方式在800nM时上调乌罗素2.7倍，标记纳摩尔范围内的最高上调。SG-02的疗效通过DMD患者来源的细胞进一步验证，显示出显著的2.3倍的utrophin表达。机械上,SG-02作为AhR拮抗剂,具有优异的结合亲和力(Kd=41.68nM)。SG-02还增强了肌生成，如MyHC表达增加所指示。ADME评估支持SG-02的口服生物利用度。总的来说,SG-02有望解决全球DMD人群的问题。
