| Autor: |
Ghosh S; Smart Healthcare Department, Interdisciplinary Research Platform, Indian Institute of Technology, Jodhpur, Rajasthan 342030, India., Arshi MU; Department of Bioscience and Bioengineering, Indian Institute of Technology, Jodhpur, Rajasthan 342030, India., Ghosh S; Department of Bioscience and Bioengineering, Indian Institute of Technology, Jodhpur, Rajasthan 342030, India., Jash M; Department of Bioscience and Bioengineering, Indian Institute of Technology, Jodhpur, Rajasthan 342030, India., Sen S; Department of Bioscience and Bioengineering, Indian Institute of Technology, Jodhpur, Rajasthan 342030, India., Mamchaoui K; Inserm, Institut de Myologie, Centre de Recherche en Myologie,Sorbonne Université, F-75013 Paris, France., Bhattacharyya S; Department of Bioscience and Bioengineering, Indian Institute of Technology, Jodhpur, Rajasthan 342030, India., Rana NK; Department of Chemistry, Indian Institute of Technology, Jodhpur, Rajasthan 342030, India., Ghosh S; Smart Healthcare Department, Interdisciplinary Research Platform, Indian Institute of Technology, Jodhpur, Rajasthan 342030, India.; Department of Bioscience and Bioengineering, Indian Institute of Technology, Jodhpur, Rajasthan 342030, India. |
| Abstrakt: |
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 ( K d = 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. |
