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: 9978103
• 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/9978103
• 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

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.

项目总结/摘要 我们的长期目标是开发针对心力衰竭（HF）的小分子疗法， 肌浆网钙-ATP酶（SERCA）。SERCA在正常心脏功能中起重要作用， 在每次心跳中清除放松肌肉细胞所需的细胞溶质钙（钙通道）。一个关键的分子功能障碍 在HF中通常涉及SERCA表达不足，导致SERCA失活和钙离子受损。 在心肌细胞中的转运。SERCA现在被广泛认为是一种治疗靶点，其激活导致 心脏功能的改善。因此，我们建议开发小分子SERCA激活剂 针对肌细胞作为恢复衰竭心脏正常功能的有效治疗方法。 这是创新的，因为发现可再生的SERCA激活剂将代表一个重大的 这是心力衰竭治疗的突破，因为它偏离了已知的当前治疗选择。我们最近 发现并验证了HF 600，一种高质量的命中，激活SERCA并刺激细胞内钙 在人iPSC心肌细胞中的转运。我们现在加强合作，并提出一个灵活，快速， 具有成本效益的药物开发战略，超越了典型的发现命中分子，以产生新的 可降解分子。我们的中心假设是，围绕HF 600的点击率优化将 产生用于HF的药理学治疗的新的治疗候选物。三个具体目标将是 本项目旨在验证这一假设：（1）在计算机中设计并合成一系列 围绕命中分子HF 600构建的可存活的SERCA激活剂;（2）评估功能性SERCA激活剂的活性。 SERCA激活剂在原位以及在人iPSC心肌细胞和动物来源的成人心室肌细胞中的活性 （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-受试者）测试。 衍生和诱导）;将通过iPSC安全性筛选和药代动力学评估SERCA激活剂 问题研究我们现在有大量的初步数据显示我们围绕HF 600构建的新SERCA激活剂 逆转患病心肌细胞中钙的错误处理，并保护其免受心律失常， 明显的长期心脏毒性这一出色的初步数据为以下方面提供了机械原理证明： 激活SERCA用于HF治疗。我们杰出的多学科团队和高度互补的方法 确保成功发现新的候选药物， 治疗心力衰竭患者。