Small Molecule Therapy for the Treatment of Heart Failure

治疗心力衰竭的小分子疗法

• 批准号: 9335758
• 负责人: Roger J. Hajjar
• 金额: $ 55.06万
• 依托单位: SUMOCOR, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-05 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9335758
• 关键词: ATP Hydrolysis; ATP phosphohydrolase; Acute; Animal Model; Benchmarking; Binding Sites; Biological; Biological Assay; Biological Availability; Ca(2+)-Transporting ATPase; Calcium; Cardiac; Cardiac Myocytes; Cells; Chemicals; Chronic; Computer Simulation; Congestive Heart Failure; Cytochrome P450; Data; Devices; Dose; Drug Compounding; Drug Interactions; Drug Kinetics; Enhancers; Enzymes; Evaluation; Excretory function; Family suidae; Gene Transfer; Generations; Goals; Heart failure; Human; In Vitro; Incidence; Lead; Ligand Binding; Ligase; Longitudinal Studies; Measurement; Metabolism; Modeling; Mus; Mutagenesis; Myocardial; Oral; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Plasma; Pre-Clinical Model; Property; Research; Rodent; Role; SERCA2a; Safety; Sarcoplasmic Reticulum; Series; Site; Structure; Structure-Activity Relationship; Testing; Toxic effect; Ubiquitin; United States; absorption; analog; base; constriction; design; drug candidate; drug discovery; hemodynamics; improved; in vitro activity; in vivo; novel; novel therapeutics; pre-clinical; pregnane X receptor; research clinical testing; scaffold; screening; small molecule; treatment strategy; virtual

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 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.

摘要