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Chemical proteomics and phenotypic profiling identifies the aryl hydrocarbon receptor as a molecular target of the utrophin modulator ezutromid
- Source :
- Angewandte Chemie (International Ed. in English)
- Publication Year :
- 2020
- Publisher :
- Wiley, 2020.
-
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.<br />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.
- 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
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Angewandte Chemie (International Ed. in English)
- Accession number :
- edsair.doi.dedup.....f40c2d310a7ebb9620d45ab78161c48d