期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 59, 期 6, 页码 2420-2428出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201912392
关键词
mechanism of action; medicinal chemistry; photoaffinity labelling; proteomics; target identification
资金
- Engineering and Physical Sciences Research Council (EPSRC) [EP/L016044/1, 1501AV003/CA2]
- Medical Research Council (MRC) [EP/L016044/1, 1501AV003/CA2]
- Summit Therapeutics
- Muscular Dystrophy UK [RA4/3013/4, RA3/30733]
- MRC [MR/N010698/1] Funding Source: UKRI
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 K-D 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.
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