Research results have been published in Angewandte Chemie.
Ezutromid (formerly SMT C1100) was identified through phenotypic screening approach, and developed as a first-in-class utrophin modulator for the treatment of the severe muscle wasting disease Duchenne muscular dystrophy (DMD). The clinical trial showed promising efficacy and evidence of target engagement after 24 weeks of treatment, but these effects were not seen after the full 48 weeks of the trial. Without knowledge of the mechanism of action of ezutromid, it was difficult to rationalise the lack of sustained clinical efficacy, and development of ezutromid was discontinued.
In this work, we demonstrate through a series of target identification and validation studies that ezutromid binds to AhR with high affinity, and antagonism of AhR by ezutromid leads to utrophin upregulation, thereby confirming AhR as a viable target for utrophin functional replacement therapies. This work paves the way for the first target-based disease modifying drug discovery program in DMD.