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Upregulation of utrophin to compensate for the missing dystrophin offers a potential therapy independent of patient genotype. The first\u2010in\u2010class 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\u2005weeks of treatment, however trial endpoints were not met after 48\u2005weeks. 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\u00a0ezutromid. Several lines of evidence demonstrate that\u00a0ezutromid\u00a0binds\u00a0AhR\u00a0with an apparent K<jats:sub>D<\/jats:sub> of 50\u2005n<jats:sc>m<\/jats:sc>\u00a0and behaves as an\u00a0AhR\u00a0antagonist. Furthermore, other reported\u00a0AhR\u00a0antagonists 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.<\/jats:p>","DOI":"10.1002\/anie.201912392","type":"journal-article","created":{"date-parts":[[2019,11,22]],"date-time":"2019-11-22T12:31:31Z","timestamp":1574425891000},"page":"2420-2428","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Chemical Proteomics and Phenotypic Profiling Identifies the Aryl Hydrocarbon Receptor as a Molecular Target of the Utrophin Modulator Ezutromid"],"prefix":"10.1002","volume":"59","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6987-3235","authenticated-orcid":false,"given":"Isabel V. 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