SBIR-STTR Award

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 Ca2+ ATPase (SERCA2a), have been found in human and animal models of HF. We have recently described a role for the small ubiquitin-like modifier type 1 (SUMO1) as a regulator of SERCA2a and have shown that gene transfer of SUMO1 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, N106, which increases SUMOylation of SERCA2a. This compound directly activates the SUMO-activating enzyme, E1 ligase, and triggers intrinsic SUMOylation of SERCA2a. We identified a pocket on SUMO E1 responsible for N106’s effects. We have completed pharmacokinetics, toxicity, and off target studies on this compound along with detailed biological activities in vivo. In Phase 1 of this Fast-Track Application, we will optimize the potency and develop the structure-activity relationships (SAR) of our lead compound based on E1 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 E1 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 2 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.

Public Health Relevance Statement:
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, SUMO1, 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.

Project Terms:
absorption; Acute; analog; Animal Model; ATP Hydrolysis; ATP phosphohydrolase; base; Benchmarking; Binding Sites; Biological; Biological Assay; Biological Availability; Ca(2+)-Transporting ATPase; Calcium; Cardiac; Cardiac Myocytes; Cells; Chemicals; Chronic; Computer Simulation; Congestive Heart Failure; constriction; Cytochrome P450; Data; design; Devices; Dose; drug candidate; Drug Compounding; drug discovery; Drug Interactions; Drug Kinetics; Enhancers; Enzymes; Evaluation; Excretory function; Family suidae; Gene Transfer; Generations; Goals; Heart failure; hemodynamics; Human; improved; In Vitro; in vitro activity; in vivo; Incidence; Lead; Ligand Binding; Ligase; Longitudinal Studies; Measurement; Metabolism; Modeling; Mus; Mutagenesis; Myocardial; novel; novel therapeutics; Oral; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Plasma; pre-clinical; Pre-Clinical Model; pregnane X receptor; Property; Research; research clinical testing; Rodent; Role; Safety; Sarcoplasmic Reticulum; scaffold; screening; SERCA2a; Series; Site; small molecule; Structure; Structure-Activity Relationship; Testing; Toxic effect; treatment strategy; Ubiquitin; United States; virtual

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 Ca2+ ATPase (SERCA2a), have been found in human and animal models of HF. We have recently described a role for the small ubiquitin-like modifier type 1 (SUMO1) as a regulator of SERCA2a and have shown that gene transfer of SUMO1 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, N106, which increases SUMOylation of SERCA2a. This compound directly activates the SUMO-activating enzyme, E1 ligase, and triggers intrinsic SUMOylation of SERCA2a. We identified a pocket on SUMO E1 responsible for N106’s effects. We have completed pharmacokinetics, toxicity, and off target studies on this compound along with detailed biological activities in vivo. In Phase 1 of this Fast-Track Application, we will optimize the potency and develop the structure-activity relationships (SAR) of our lead compound based on E1 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 E1 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 2 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.

Public Health Relevance Statement:
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, SUMO1, 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.

Project Terms:
absorption; Acute; analog; Animal Model; ATP Hydrolysis; ATP phosphohydrolase; base; Benchmarking; Binding Sites; Biological; Biological Assay; Biological Availability; Ca(2+)-Transporting ATPase; Calcium; Cardiac; Cardiac Myocytes; Cells; Chemicals; Chronic; Computer Simulation; Congestive Heart Failure; constriction; Cytochrome P450; Data; design; Devices; Dose; drug candidate; Drug Compounding; drug discovery; Drug Interactions; Drug Kinetics; Enhancers; Enzymes; Evaluation; Excretory function; Family suidae; Gene Transfer; Generations; Goals; Heart failure; heart function; hemodynamics; Human; human model; improved; In Vitro; in vitro activity; in vivo; Incidence; Lead; Ligand Binding; Ligase; Longitudinal Studies; Measurement; Metabolism; Modeling; Mus; Mutagenesis; Myocardial; novel; novel therapeutics; Oral; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Plasma; pre-clinical; Pre-Clinical Model; pregnane X receptor; Property; Research; research clinical testing; Rodent; Role; Safety; Sarcoplasmic Reticulum; scaffold; screening; screening panel; SERCA2a; Series; Site; small molecule; Structure; Structure-Activity Relationship; Testing; Toxic effect; treatment strategy; Ubiquitin; United States; virtual