Abstract
AbstractDuchenne muscular dystrophy (DMD) is a fatal muscle‐wasting disease arising from mutations in the dystrophin gene. Upregulation of utrophin to compensate for the missing dystrophin offers a potential therapy independent of patient genotype. The first‐in‐class utrophin modulator ezutromid/SMT C1100 was developed from a phenotypic screen through to a Phase 2 clinical trial. Promising efficacy and evidence of target engagement was observed in DMD patients after 24 weeks of treatment, however trial endpoints were not met after 48 weeks. The objective of this study was to understand the mechanism of action of ezutromid which could explain the lack of sustained efficacy and help development of new generations of utrophin modulators. Using chemical proteomics and phenotypic profiling we show that the aryl hydrocarbon receptor (AhR) is a target of ezutromid. Several lines of evidence demonstrate that ezutromid binds AhR with an apparent KD of 50 nm and behaves as an AhR antagonist. Furthermore, other reported AhR antagonists also upregulate utrophin, showing that this pathway, which is currently being explored in other clinical applications including oncology and rheumatoid arthritis, could also be exploited in future DMD therapies.
Highlights
Duchenne muscular dystrophy (DMD) is a fatal, X-linked muscle wasting disease that affects approximately 1 in 3500– 5000 boys.[1,2] DMD is caused by loss-of-function mutations in the dystrophin gene
Duchenne muscular dystrophy (DMD) is a fatal muscle-wasting disease arising from mutations in the dystrophin gene
The first-in-class utrophin modulator ezutromid/SMT C1100 was developed from a phenotypic screen through to a Phase 2 clinical trial
Summary
Duchenne muscular dystrophy (DMD) is a fatal, X-linked muscle wasting disease that affects approximately 1 in 3500– 5000 boys.[1,2] DMD is caused by loss-of-function mutations in the dystrophin gene. Developments in the clinical standard of care have led to improvements in quality of life and longevity[7,8,9] but there is currently no available cure for DMD. Several therapeutic strategies have reached the clinic, including stop codon readthrough and exon skipping which target particular mutations, and gene therapy which faces multiple challenges, including viral production and immune response.[10,11]
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