1. Chemical proteomics and phenotypic profiling identifies the aryl hydrocarbon receptor as a molecular target of the utrophin modulator ezutromid
- Author
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Kelly J. Perkins, Stephen G. Davies, P Burch, Wilkinson Ivl., Philip D. Charles, A Lomow, S Monecke, Graham Michael Wynne, Shabaz Mohammed, Sarah E. Squire, Maria Chatzopoulou, Kay E. Davies, A Vuorinen, M Geese, H Dugdale, Fraydoon Rastinejad, Lee Moir, F. Wilson, Angela J. Russell, and Jonathon M. Tinsley
- Subjects
Proteomics ,Utrophin ,Duchenne muscular dystrophy ,01 natural sciences ,Myoblasts ,Mice ,0302 clinical medicine ,Research Articles ,0303 health sciences ,Benzoxazoles ,Cycloaddition Reaction ,General Medicine ,3. Good health ,Up-Regulation ,medicine.symptom ,Dystrophin ,Protein Binding ,Research Article ,musculoskeletal diseases ,Phenotypic screening ,Biology ,Naphthalenes ,010402 general chemistry ,Catalysis ,03 medical and health sciences ,Downregulation and upregulation ,target identification ,medicine ,Animals ,Humans ,photoaffinity labelling ,030304 developmental biology ,010405 organic chemistry ,General Chemistry ,medicine.disease ,Aryl hydrocarbon receptor ,0104 chemical sciences ,Muscular Dystrophy, Duchenne ,Kinetics ,Mechanism of action ,Receptors, Aryl Hydrocarbon ,Drug Design ,Molecular Probes ,biology.protein ,Cancer research ,Medicinal Chemistry ,030217 neurology & neurosurgery ,mechanism of action - Abstract
Duchenne 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., Chemical proteomics and phenotypic profiling illustrate the aryl hydrocarbon receptor (AhR) is a target of ezutromid, the first‐in‐class utrophin modulator for the treatment of Duchenne muscular dystrophy. Ezutromid binds to AhR with an apparent K D of 50 nm and functions as an AhR antagonist. Other reported AhR antagonists also upregulate utrophin, showing that this pathway, which is currently being explored in other clinical applications, could also be exploited in future DMD therapies.
- Published
- 2020