Development of next generation utrophin modulators for Duchenne muscular dystrophy: learning from clinical setbacks<\/b><\/p>\n
Abstract<\/b>: 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.\u00a0There is currently no cure for DMD, although various promising approaches (e.g.\u00a0exon skipping, read through of stop codons, gene therapy) are being developed.\u00a0We 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.\u00a0In partnership with Summit Therapeutics, the 2-aryl benzoxazole utrophin modulator\u00a0ezutromid\u00a0(formerly SMT C1100)\u00a0identified through a phenotypic screening approach,\u00a0was\u00a0progressed to human clinical trials\u00a0as 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\u00a0ezutromid, it was difficult to\u00a0rationalise\u00a0the lack of sustained clinical efficacy, and development of\u00a0ezutromid\u00a0was discontinued.\u00a0\u00a0This talk will provide an overview of the\u00a0early discovery and the clinical translation of\u00a0ezutromid, 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\u00a0ezutromid.\u00a0Our demonstration through a series of target identification and validation studies that\u00a0ezutromid\u00a0binds to the\u00a0arylhydrocarbon\u00a0receptor (AhR) with high affinity, and antagonism of\u00a0AhR\u00a0by\u00a0ezutromid\u00a0leads to utrophin upregulation will be described, confirming\u00a0AhR\u00a0as a viable target for utrophin functional replacement therapies. The identification of new lead molecule\u00a0AhR\u00a0antagonists with better efficacy and improved properties compared to\u00a0ezutromid\u00a0will 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\u00a0ezutromid.<\/p>\n
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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.\u00a0There is currently no cure for DMD, although various promising approaches (e.g.\u00a0exon skipping, read through…<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[1],"tags":[],"post_series":[],"class_list":["post-494","post","type-post","status-publish","format-standard","hentry","category-sem-categoria","entry","no-media"],"_links":{"self":[{"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/posts\/494","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/comments?post=494"}],"version-history":[{"count":1,"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/posts\/494\/revisions"}],"predecessor-version":[{"id":495,"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/posts\/494\/revisions\/495"}],"wp:attachment":[{"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/media?parent=494"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/categories?post=494"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/tags?post=494"},{"taxonomy":"post_series","embeddable":true,"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/post_series?post=494"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}