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.