Hit-to-lead optimization for heart failure drug discovery

心力衰竭药物发现的先导化合物优化

• 批准号: 10201740
• 负责人: Lennane Michel Espinoza-Fonseca
• 金额: $ 72.43万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-17 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201740
• 关键词: 3-Dimensional; ATP phosphohydrolase; Address; Adult; Animals; Area; Arrhythmia; Biological Assay; Ca(2+)-Transporting ATPase; Calcium; Cardiac; Cardiac Myocytes; Cardiology; Cardiotoxicity; Cardiovascular system; Cells; Cellular Assay; Characteristics; Chemistry; Clinical Research; Collaborations; Computers; Computing Methodologies; Data; Defect; Diastole; Disease; Dose; Drug Design; Drug Kinetics; Ensure; Excretory function; Functional disorder; Goals; Heart; Heart Diseases; Heart failure; Human; Hypertrophic Cardiomyopathy; Impairment; In Situ; In Vitro; Laboratories; Lead; Long-Term Effects; Medicine; Membrane Proteins; Metabolism; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mus; Muscle; Muscle Cells; Outcome; Patients; Peripheral; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Play; Process; Property; Pump; Reperfusion Injury; Research; Role; Safety; Sarcoplasmic Reticulum; Series; Solid; Symptoms; Testing; Therapeutic; Treatment Efficacy; Treatment Failure; United States; Validation; Ventricular; absorption; clinical application; cost effective; design; drug development; drug discovery; flexibility; functional restoration; heart function; improved; in silico; in vitro testing; in vivo; induced pluripotent stem cell; innovation; lead optimization; monolayer; mortality; multidisciplinary; novel; novel therapeutics; preclinical study; response; sarcoplasmic reticulum calcium ATPase; screening; small molecule; small molecule therapeutics; success; synergism; therapeutic candidate; therapeutic target; therapeutically effective

PROJECT SUMMARY/ABSTRACT Our long-term goal is to develop small-molecule therapies for heart failure (HF) that target the cardiac sarcoplasmic reticulum calcium-ATPase (SERCA). SERCA plays an essential role in normal cardiac function, clearing cytosolic calcium needed to relax muscle cells in each heart beat (diastole). A key molecular dysfunction in HF usually involves insufficient SERCA expression, leading to SERCA inactivation and impaired calcium transport in the cardiomyocyte. SERCA is now widely recognized as a therapeutic target, and its activation results in improved cardiac function in HF models. Therefore, we propose to develop small-molecule SERCA activators directed at the myocyte as an effective therapeutic approach for restoring normal function in the failing heart. This is innovative because discovery of pharmacologically viable SERCA activators would represent a major breakthrough in therapies for heart failure, as it deviates from known current therapeutic options. We recently discovered and validated HF600, a high-quality hit that activates SERCA and stimulates intracellular calcium transport in human iPSC cardiomyocytes. We now intensify our collaboration and propose a flexible, fast and cost-effective drug development strategy beyond the typical discovery of hit molecules to generate novel pharmacologically viable molecules. Our central hypothesis is that hit-to-lead optimization around HF600 will produce novel therapeutic candidates for the pharmacological treatment of HF. Three specific aims will be pursued in this project to test this hypothesis: (1) design in the computer and synthesize series of pharmacologically viable SERCA activators built around the hit molecule HF600; (2) evaluate the functional activity of SERCA activators in situ, and in both human iPSC cardiomyocytes and animal-derived adult ventricular myocytes; and (3) determine therapeutic efficacy, safety and pharmacokinetics of SERCA activators. Therapeutic efficacy of small-molecule candidates will be tested using diseased iPSC cardiomyocytes (patient- derived and induced); SERCA activators will be evaluated through iPSC safety screening and pharmacokinetics studies. We now have extensive preliminary data showing that a new SERCA activator we built around HF600 reverses calcium mishandling in the diseased cardiomyocyte, and also protects it against arrhythmia with no apparent long-term cardiotoxicity. This excellent preliminary data provides mechanistic proof-of-principle for activating SERCA for HF therapy. Our outstanding multidisciplinary team and highly complementary approaches on a validated pharmacological target ensure successful discovery of novel candidates for the pharmacological treatment of patients with heart failure.

项目摘要/摘要 我们的长期目标是开发针对心脏的心力衰竭（HF）的小分子疗法 肌质网钙ATPase（SERCA）。 SERCA在正常心脏功能中起着至关重要的作用， 清除胞质钙需要放松每个心脏跳动（舒张期）中的肌肉细胞。关键分子功能障碍 在HF中，通常涉及SERCA表达不足，导致SERCA失活和钙受损 心肌细胞中的运输。 SERCA现在被广泛认为是治疗靶标，其激活结果 在改善HF模型中的心脏功能中。因此，我们建议开发小分子SERCA激活剂 针对肌细胞是一种有效的治疗方法，用于恢复失败的心脏中正常功能。 这是创新的，因为发现药理学可行的SERCA激活剂将代表主要 由于它偏离了已知的当前治疗选择，因此心力衰竭的疗法突破。我们最近 发现并验证了HF600，这是一种激活SERCA并刺激细胞内钙的高质量命中 人IPSC心肌细胞中的运输。现在，我们加强了我们的协作，并提出灵活，快速和 除了典型发现HIT分子以产生新颖的药物开发策略以外的药物开发策略 药理学上可行的分子。我们的中心假设是HF600周围的命中率优化 生产新的治疗候选者，用于HF的药理治疗。三个具体目标将是 在该项目中追求以检验此假设：（1）在计算机中设计并合成一系列 围绕命中分子HF600建立的药理学可行的SERCA激活剂； （2）评估功能 SERCA激活剂的活性，在人IPSC心肌细胞和动物衍生的成年心室 心肌细胞； （3）确定SERCA激活剂的治疗功效，安全性和药代动力学。 小分子候选物的治疗功效将使用患病的IPSC心肌细胞（患者 - 派生和诱导）； SERCA激活剂将通过IPSC安全筛选和药代动力学评估 研究。现在，我们拥有广泛的初步数据，表明我们围绕HF600构建的新Serca激活剂 逆转患病的心肌细胞中的钙不当，也可以保护其免受心律不齐 明显的长期心脏毒性。这个出色的初步数据为原则机理证明了 激活SERCA进行HF治疗。我们杰出的多学科团队和高度互补的方法 在经过验证的药理学目标上确保成功发现了药理学的新候选物 心力衰竭患者的治疗。