PROGENRA INC — Department of Health and Human Services SBIR Phase II: 300

Description

DESCRIPTION provided by applicant The ubiquitin proteasome pathway degrades of cellular proteins and is of great interest as a source of new therapeutics for multiple diseases The pre proteasomal phase of the pathway catalyzed by the ubiquitin E activating enzyme E conjugating enzyme and E ligase is predicted to afford drugs that act more selectively than proteasome inhibitors the first class of drug developed from the ubiquitin proteasome pathway and thus be less compromised than proteasome inhibitors by side effects Evidence implicates E enzymes in various physiological processes and disease states For these reasons major pharmaceutical companies have spent several years identifying novel selective E inhibitors for drug development but to date the results have been disappointing as very few E inhibitors have entered clinical trials Reasoning that improved assays were needed to discover high quality molecules in screening Progenra developed in Phase I of this grant project facile homogeneous assays for E ligases of choice including an screen based assay that can be employed for substrate ubiquitylation as well as auto ubiquitylation The E ligase whose physiological substrate Troponin I was configured for the substrate based assay is the simple RING finger E MuRF which is associated with muscle wasting or myopathy a pathological complication of numerous diseases including cancer HIV AIDS and diabetes as well as a natural consequence of inactivity and aging Muscle wasting is a result of increased rates of protein breakdown and decreased rates of protein synthesis with a secondary net loss in muscle weight of MuRF is one of several genes overexpressed in myopathy and it is a well validated target for therapeutic agents to treat muscle wasting In the phase II year project it is proposed to utilize the MuRF Troponin I assay developed in Phase I to screen Progenraandapos s member small molecule library for inhibitors of this substrate ubiquitylation These inhibitors will be characterized using secondary assays to establish selectivity and efficacy Initial preclinical evaluation will be performed using in vitro and in vivo models of muscle wasting and medicinal chemistry will be employed for lead optimization The identification of specific inhibitors of MuRF will be an important first step in producing novel targeted therapies for muscle atrophy PUBLIC HEALTH RELEVANCE Progenra proposes to utilize a recently developed assay to find inhibitors of MuRF a ubiquitin pathway enzyme implicated in muscle wasting cachexia a severe complication of many diseases and aging The assay was developed in Phase I of this SBIR project and in Phase II it will be employed in high throughput mode to develop clinical candidate inhibitors to treat muscle wasting