Résumé :
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PTC Therapeutics, Inc. (PTC) and Parent Project Muscular Dystrophy (PPMD) are collaborating to discover new drugs to treat Duchenne muscular dystrophy (DMD). Several targets were selected to enter the drug discovery program based on functional validation from animal studies. The targets selected for high throughput screening (HTS) included: utrophin (UTRN), muscle-specific insulin-like growth factor (mIGF1), and ?7 integrin (ITGA7). Using a proprietary drug discovery platform technology, referred to as GEMS (Gene Expression Modulation by Small-molecules), we sought to identify small molecules that upregulate the production of these protein targets to identify potential treatments for DMD. Constructs containing the firefly luciferase (fLuc) reporter gene flanked by the 5’ and 3’ untranslated regions (UTR) specific for each of the targets were stably transfected in human muscle (RD) or kidney (293H) cells and used in HTS. We identified hits that demonstrate concentration dependent activities in cell-based reporter assays and in assays that measure protein levels. Further, a number of molecules exhibit good pharmacological properties (e. g., low cytotoxicity and microsome metabolic stability). Presently, we are focused on optimizing the activity, potency and pharmacological properties of 2 chemical scaffolds for the mIGF1 program which exhibit up to 5 fold upregulation of mIGF1 and demonstrate structure-activity relationships. For UTRN and ITGA7, we have identified 2 chemical scaffolds for each target and are in the process of establishing structure-activity relationships for these chemical classes. The ultimate goal of this drug discovery and development effort is to identify small molecules that can specifically modulate the production of a number of proteins that can be used as monotherapy or as part of a combination therapy to treat Duchenne muscular dystrophy.
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