Unveiling Hope: Novel Small Molecules as Utrophin Upregulators in the Pursuit of DMD Therapeutics.


Translational Research

Poster Number: V72


Surojit Ghosh, Research Fellow, Indian Institute of Technology Jodhpur, Surajit Ghosh, PhD, Indian Institute of Technology Jodhpur

Introduction: Duchenne muscular dystrophy (DMD) is a debilitating and life-threatening condition resulting from the deficiency of dystrophin, a vital cytoskeletal protein. The upregulation of utrophin, a paralogue protein for dystrophin, is a promising therapeutic avenue for DMD treatment, regardless of mutation type.
Objectives: To design, synthesize, and validate novel small molecules that could upregulate utrophin protein at the lowest optimal concentration.
Results: In this study, we detail the development, synthesis, and validation of novel small molecules serving as potent utrophin modulators in the nanomolar range. Through high-throughput In-Cell ELISA screening in C2C12 cell lines, out of seventy molecules synthesized, our hit molecule SG-02 demonstrated robust utrophin upregulation, more than 2.5 fold in a dose-dependent manner. Validation in a human cell line derived from DMD patients further confirmed significant utrophin expression. The mechanism of action establishes that SG-02 acts as an AhR antagonist with a significant binding affinity. Additionally, SG-02 exhibited enhanced myogenesis, validated by elevated Myosin heavy chain (MHC) expression through Immunocytochemistry. A preliminary ADME assessment performed supports SG-02 as a promising oral bioavailable therapeutic.
Conclusion: Altogether, SG-02 has enormous potential to emerge as a suitable drug candidate for treating the global DMD population, irrespective of the type of mutations. The dual efficacy demonstrated by SG-02 underscores its potential in both utrophin upregulation and myogenesis. This suggests a promising avenue for SG-02 as a therapeutic candidate with multifaceted benefits in the context of treating Duchenne muscular dystrophy (DMD).