Small Molecule Therapy for the Treatment of Heart Failure

ABSTRACT The incidence of heart failure HF continues to increase in the United States despite significant advances in pharmacological therapies and novel devices There is an acute need for novel treatment strategies for heart failure A key abnormality in HF is defective handling of calcium that has been partially related to abnormal sarcoplasmic reticulum SR function in cardiac myocytes Reduced expression and altered activity of the cardiac sarcoplasmic reticulum Ca ATPase SERCA a have been found in human and animal models of HF We have recently described a role for the small ubiquitin like modifier type SUMO as a regulator of SERCA a and have shown that gene transfer of SUMO in rodents and large animal models of heart failure restores cardiac function Through an extensive small molecule screen we have identified and characterized a small molecule N which increases SUMOylation of SERCA a This compound directly activates the SUMO activating enzyme E ligase and triggers intrinsic SUMOylation of SERCA a We identified a pocket on SUMO E responsible for N s effects We have completed pharmacokinetics toxicity and off target studies on this compound along with detailed biological activities in vivo In Phase of this Fast Track Application we will optimize the potency and develop the structure activity relationships SAR of our lead compound based on E ligase ATP activity and contractile function in cardiac myocytes and in animal models We have used computational modeling to perform in silico screening of the validated E enzyme pocket to generate new compounds and new scaffolds for further evaluation Medicinal chemistry will be used to further expand the chemical series from proof of concept compounds to a fully characterized compound for IND enabling studies In Phase of this Fast Track Application we will test the effects of the leading candidates in rodent and large animal models of heart failure Our long term goal is to develop potent drugs to treat acute and chronic HF Our overall objective is to drive translational drug discovery from lead scaffolds to candidate compounds for SUMOCOR which can be taken forward for clinical testing in patients with HF PROJECT NARRATIVE The incidence of congestive heart failure continues to increase in the United States despite significant advances in pharmacological therapies and novel devices Our overall objective is to use our discovery of a new pathway involved in heart failure SUMO in order to discover novel drug compounds Our long term goal at SUMOCOR LLC is to develop efficacious drugs to treat acute and chronic heart failure