P.308 - Discovery of small molecule utrophin modulators for the therapy of Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a devastating, X-linked muscle-wasting disease caused by lack of the cytoskeletal 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. By transcriptionally reprogramming the temporal and spatial expression of the dystrophin-related protein utrophin, we aim to develop a pharmacological therapy applicable to all DMD patients by targeting the primary defect. In partnership with Summit Therapeutics, the utrophin modulator ezutromid (formerly SMT C1100), which demonstrates reduced dystrophic symptoms in the mdx mouse, has progressed to human clinical trials. As a potential First-In-Class molecule, ezutromid is currently being evaluated in an open label phase 2 trial in DMD patients. A series of second generation utrophin modulators which are structurally similar to ezutromid, but with improved physicochemical and metabolism profiles have been evaluated in the mdx mouse, and results were published recently. Novel utrophin modulator chemotypes have also been discovered using an alternative in vitro dystrophin null myoblast screening assay where the reporter gene has been directly knocked into a utrophin exon. New structural classes which increase utrophin expression in both murine and human DMD myoblasts have been identified and are now being optimised. Initial evidence suggests that some of these small molecules modulate utrophin transcription through an alternative regulatory mechanism to ezutromid. These new compounds exhibit favourable properties and are well tolerated in the mdx mouse. SAR studies are underway, with the objective to improve compound effectiveness and exposure.