Muscle atrophy (wasting), also known as myopathy, is a clinical complication of many diseases, e.g., cancer, AIDS, and diabetes, as well as a natural consequence of inactivity and aging;it significantly diminishes quality of life. The expression of a group of novel genes called atrogins (atrophy-specific genes) increases dramatically in skeletal muscles of fasting organisms and decreases rapidly upon resumption of feeding. One of these, MuRF-1 (Muscle-specific RING Finger- 1), has been identified as an E3 ubiquitin ligase that is a component of atrophy-associated accelerated proteolysis. Ubiquitin pathway enzymes are considered excellent molecular targets for diverse indications, Thus, MuRF-1 is an attractive target for preventing or reversing muscle wasting associated with various pathologies. Progenra proposes to utilize an assay developed in Phase I to screen small molecule libraries to identify inhibitors of MuRF-1 and optimize them chemically. In this supplemental project, it is proposed to extend the scope of the Phase II project and shorten the preclinical development time of MuRF-1 inhibitors by characterizing selected inhibitors in functional assays, including cell-based (C2C12 myotubes) assays and in vivo efficacy models of muscle wasting. The identification of clinical candidate inhibitors of MuRF-1 is the first step in the development of a class of novel targeted therapies for muscle wasting. These therapies should be efficacious in treating muscle wasting associated with aging, cancer, diabetes, and other chronic conditions.
Muscle atrophy (wasting), also known as myopathy, is a clinical complication of many diseases, e.g., cancer, AIDS, and diabetes, as well as a natural consequence of inactivity and aging;it significantly diminishes quality of life. Progenra has developed a screening assay to find inhibitors of an enzyme (called MuRF-1) that is associated with muscle protein degradation. Phase II work will consist of using this assay to find suitable inhibitors and making them drug-like by applying medicinal chemistry. In this supplemental project, the best of these inhibitors of MuRF-1 will be tested in cellular and animal models of muscle wasting as an initial step in their pre-clinical development;this will shorten the time it takes to move them into clinical trials. Ultimately, one of these compounds may advance to the clinic and market for the treatment of muscle wasting.
| Goldenberg, Seth J; Marblestone, Jeffrey G; Mattern, Michael R et al. (2010) Strategies for the identification of ubiquitin ligase inhibitors. Biochem Soc Trans 38:132-6 |
