Hit-to-lead optimization for heart failure drug discovery

项目摘要/摘要 我们的长期目标是开发针对心脏衰竭(HF)的小分子疗法。 肌浆网钙-ATPase(SERCA)。SERCA在正常的心脏功能中起着至关重要的作用， 清除细胞内钙需要放松每一次心跳(舒张期)中的肌细胞。一种关键的分子功能障碍 在HF中，通常涉及SERCA表达不足，导致SERCA失活和钙损伤 在心肌细胞中的运输。SERCA现在被广泛认为是一个治疗靶点，它的激活结果 改善心力衰竭模型的心功能。因此，我们建议开发小分子SERCA激活剂 针对心肌细胞，作为恢复衰竭心脏正常功能的有效治疗方法。 这是创新的，因为发现药理上可行的SERCA激活剂将是一项重要的 心力衰竭治疗方面的突破，因为它偏离了目前已知的治疗方案。我们最近 发现并验证了HF600，一种激活SERCA并刺激细胞内钙离子的高质量HIT 在人ipsc心肌细胞中的转运。我们现在加强合作，提出灵活、快速和 性价比高的药物开发策略超越了典型的发现命中分子产生新的 药理上可行的分子。我们的中心假设是，围绕HF600的成功到领先的优化将 为心力衰竭的药物治疗创造新的候选治疗方法。三个具体目标将是 在这个项目中追求来检验这个假设：(1)在计算机中设计和合成一系列 围绕HIT分子HF600构建的药理上可行的SERCA激活剂；(2)评估功能 SERCA激活剂在人IPSC心肌细胞和动物来源的成人心肌细胞中的活性 (3)确定SERCA激动剂的疗效、安全性和药代动力学。 小分子候选药物的治疗效果将使用患病的IPSC心肌细胞(患者- 衍生和诱导)；SERCA激活剂将通过IPSC安全筛选和药代动力学进行评估 学习。我们现在有大量的初步数据显示，我们在HF600附近建立的一个新的SERCA激活剂 逆转病变心肌细胞中钙的不当处理，并保护其免受心律失常的影响 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的原则证明 激活SERCA用于心衰治疗。我们卓越的多学科团队和高度互补的方法 有效的药理靶点确保成功发现新的药理候选药物 心力衰竭患者的治疗。

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.