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 在美国，心力衰竭（HF）的发病率持续增加，尽管在以下方面取得了显著进展： 药理学疗法和新设备。目前迫切需要新的心脏病治疗策略 失败HF中的一个关键异常是钙的处理缺陷，其部分与异常 肌浆网（SR）功能在心肌细胞。减少的表达和改变的活性， 心肌肌浆网Ca 2 + ATP酶（SERCA 2a），已在人类和动物模型中发现， HF。我们最近描述了小泛素样修饰物1型（SUMO 1）作为调节剂的作用， SERCA 2a和SUMO 1的基因转移在啮齿类动物和心力衰竭的大型动物模型中显示， 恢复心脏功能通过广泛的小分子筛选，我们已经鉴定并表征了 小分子N106，其增加SERCA 2a的SUMO化。这种化合物直接激活 SUMO激活酶，E1连接酶，并触发SERCA 2a的内在SUMO化。我们发现了一个口袋 对N106的影响负责我们已经完成了药代动力学毒性和脱靶试验 对该化合物的研究沿着而来的是详细的体内生物活性。在本快速通道的第一阶段， 应用，我们将优化效力并发展我们的先导化合物的结构-活性关系（SAR） 在心肌细胞和动物模型中，基于E1连接酶ATP活性和收缩功能的化合物。 我们已经使用计算机建模对经验证的E1酶口袋进行了计算机筛选， 产生新的化合物和新的支架用于进一步评估。药物化学将用于进一步 将化学系列从概念验证化合物扩展到IND的完全表征化合物， 赋能研究。在此快速通道应用程序的第二阶段，我们将测试领先候选人在以下方面的效果： 啮齿动物和大型动物心力衰竭模型。我们的长期目标是开发有效的药物来治疗急性 慢性HF。我们的总体目标是推动翻译药物发现从领先的支架，到候选人 SUMOCOR的化合物，其可用于HF患者的临床试验。