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Development of next generation utrophin modulators for Duchenne muscular dystrophy: learning from clinical setbacks

Abstract: Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle wasting disorder caused by mutations in the dystrophin locus leading to absence of the associated protein, dystrophin. There is currently no cure for DMD, although various promising approaches (e.g. exon skipping, read through of stop codons, gene therapy) are being developed. We and others have demonstrated that DMD pathology in preclinical models can be prevented through functional replacement of dystrophin with its autosomal paralogue, utrophin. Our long-term therapeutic aim is to develop a small molecule drug to increase utrophin levels at the muscle membrane in DMD patients. In partnership with Summit Therapeutics, the 2-aryl benzoxazole utrophin modulator ezutromid (formerly SMT C1100) identified through a phenotypic screening approach, was progressed to human clinical trials as our first-in-class utrophin modulator. The clinical trial showed promising efficacy and evidence of target engagement after 24 weeks of treatment, but these effects were not seen after the full 48 weeks of the trial. Without knowledge of the mechanism of action of ezutromid, it was difficult to rationalise the lack of sustained clinical efficacy, and development of ezutromid was discontinued.  This talk will provide an overview of the early discovery and the clinical translation of ezutromid, our follow up work to rationalise the lack of sustained efficacy in the clinic, and our development of follow-on compounds to overcome the limitations of ezutromid. Our demonstration through a series of target identification and validation studies that ezutromid binds to the arylhydrocarbon receptor (AhR) with high affinity, and antagonism of AhR by ezutromid leads to utrophin upregulation will be described, confirming AhR as a viable target for utrophin functional replacement therapies. The identification of new lead molecule AhR antagonists with better efficacy and improved properties compared to ezutromid will also be described, as will the implementation of an alternative screening strategy leading to the discovery of new molecules with a distinct mechanism of action to ezutromid.

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