Development of novel small molecules for delaying the progression of muscular dy

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Description (provided by applicant): The purpose of this proposal is to develop new small molecule drugs for the treatment of Duchenne, and possibly other muscular dystrophies. We have chosen four targets that can alter the disease process if the protein levels are either increased or decreased. Our four targets are: utrophin (UTRN), myostatin (GDF8), the class la splice-form of insulin-like growth factor (IGF-la), and <x7-integrin (ITGA7). Work by others (and in some cases ourselves) has demonstrated that a modest increase in the levels of utrophin, IGF-la or ITGA7 can significantly improve the muscle weakness associated with mutations in the dystrophin and/or UTRN genes in mice. Similarly, inhibition of GDF8 has been shown to improve muscle growth and regeneration in mice harboring a mutation in the dystrophin gene (mdx) mice. We have constructed this U54 proposal with one overarching project and four cores to perform (1) medicinal chemistry; (2) pharmacology; (3) toxicology; and (4) efficacy assessment of potential drugs to modulate our four targets. We have used the Gene Expression Modulation by Small molecules (GEMS) technology in a high-throughput screening (HTS) platform to identify small molecules that modulate expression of our targets that have been validated in animal models of muscular dystrophy. We have discovered multiple compounds via the HTS that modulate our four targets in muscle cells in culture. We now need to begin the iterative process that will turn these initial hits into drugs. Thus, the ultimate goal of this research proposal is to identify, characterize and optimize small molecules that can be used in a clinical setting to treat muscular dystrophy.