Small Molecule Therapy for the Treatment of HeartFailure

The incidence of heart failureHFcontinues to increase in the United States despite significant advances in pharmacological therapies and novel devicesThere is an acute need for novel treatment strategies for heart failureA key abnormality in HF is defective handling of calcium that has been partially related to abnormal sarcoplasmic reticulumSRfunction in cardiac myocytesReduced expression and altered activity of the cardiac sarcoplasmic reticulum CaATPaseSERCA ahave been found in human and animal models of HFWe have recently described a role for the small ubiquitin like modifier typeSUMOas a regulator of SERCA a and have shown that gene transfer of SUMOin rodents and large animal models of heart failure restores cardiac functionThrough an extensive small molecule screenwe have identified and characterized a small moleculeNwhich increases SUMOylation of SERCA aThis compound directly activates the SUMO activating enzymeEligaseand triggers intrinsic SUMOylation of SERCA aWe identified a pocket on SUMO Eresponsible for Ns effectsWe have completed pharmacokineticstoxicityand off target studies on this compound along with detailed biological activities in vivoIn Phaseof this Fast Track Applicationwe will optimize the potency and develop the structure activity relationshipsSARof our lead compound based on Eligase ATP activity and contractile function in cardiac myocytes and in animal modelsWe have used computational modeling to perform in silico screening of the validated Eenzyme pocket to generate new compounds and new scaffolds for further evaluationMedicinal chemistry will be used to further expand the chemical series from proof of concept compounds to a fully characterized compound for IND enabling studiesIn Phaseof this Fast Track Applicationwe will test the effects of the leading candidates in rodent and large animal models of heart failureOur long term goal is to develop potent drugs to treat acute and chronic HFOur overall objective is to drive translational drug discovery from lead scaffoldsto candidate compounds for SUMOCORwhich can be taken forward for clinical testing in patients with HF The incidence of congestive heart failure continues to increase in the United States despite significant advances in pharmacological therapies and novel devicesOur overall objective is to use our discovery of a new pathway involved in heart failureSUMOin order to discover novel drug compoundsOur long term goal at SUMOCOR LLC is to develop efficacious drugs to treat acute and chronic heart failure