Hit to Lead Optimization of Small Molecule Therapeutics for Muscular Dystrophy

DESCRIPTION (provided by applicant): Defective adhesion between the interior and exterior of skeletal myofibers is a common etiological event in many forms of muscular dystrophy, and may arise from defects in cytoskeletal proteins such as dystrophin and plectin, membrane proteins such as the sarcoglycans and alpha dystroglycan, or extracellular matrix proteins such as laminin-211 and collagen VI. Gene and stem cell therapy, mRNA rescue technologies such as Ataluren and exon skipping, and small molecule enhancement of the so-called booster genes such as utrophin, alpha7 integrin and GALGT are among the approaches to treat Duchenne muscular dystrophy (DMD). High throughput screens for small molecules that enhance utrophin and the alpha7 integrin are at the most advanced stage of development, and this proposal will focus upon small molecules that enhance the alpha7 integrin. There are many advantages to our approach; [1] enhancement of the alpha7 integrin has proven to ameliorate the progression of muscular dystrophy in mouse models, [2] all DMD patients as well as patients with other forms of muscular dystrophy express the alpha7 integrin, [3] unlike gene or stem cell therapy enhanced alpha7 integrin is not expected to elicit an immune response, [4] small molecule enhancement of alpha7 integrin and other booster genes should benefit those patients who will not respond to Ataluren or exon skipping, [5] intervention with orally available compounds should facilitate patient compliance, and lastly [6] small molecules typically have a uncomplicated development path. Prothelia has licensed the rights to develop and commercialize compounds which enhance the expression of the alpha7 integrin, and this proposal seeks funding to perform the hit to lead optimization of these parent chemical scaffolds. Each of these scaffolds will be prioritized according to acceptable absorption, distribution, metabolism, excretion and toxicity (ADMET) criteria. Analogs of the parent scaffolds will be synthesized, revalidated in the primary alpha7 integrin screen and basic ADMET screens, followed by more advanced ADMET screening assays. Those compound(s) shown to be fully optimized will be subsequently evaluated in pre-IND safety and efficacy studies for an anticipated clinical trial for treatment of Duchenne muscular dystrophy (DMD) and/or congenital muscular dystrophy type 1A (MDC1A) and 1D (MDC1D). PUBLIC HEALTH RELEVANCE: This proposal will perform hit to lead optimization of a small molecule scaffold that enhanced the expression of the alpha7 integrin, a protein known to ameliorate the manifestations of Duchenne muscular dystrophy (DMD). If we are successful the optimized lead small molecule will be evaluated in pre-IND efficacy and toxicity studies followed by an anticipated clinical trial for DMD.