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

基本信息

批准号：
10442431
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-17 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10442431
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

项目摘要

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.

项目概要/摘要我们的长期目标是开发针对心脏功能的心力衰竭 (HF) 小分子疗法肌浆网钙-ATP 酶 (SERCA)。 SERCA 在正常心脏功能中发挥着重要作用，清除每次心跳（舒张期）时放松肌肉细胞所需的胞质钙。关键分子功能障碍心力衰竭通常涉及 SERCA 表达不足，导致 SERCA 失活和钙离子受损心肌细胞内的运输。 SERCA现已被广泛认为是治疗靶点，其激活结果改善心力衰竭模型的心脏功能。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。这是创新性的，因为药理学上可行的 SERCA 激活剂的发现将代表一个重大的进展。心力衰竭治疗的突破，因为它偏离了当前已知的治疗方案。我们最近发现并验证了 HF600，这是一种高品质的热门产品，可激活 SERCA 并刺激细胞内钙人 iPSC 心肌细胞中的转运。我们现在加强合作并提出灵活、快速和经济有效的药物开发策略超越了典型的命中分子发现，以产生新的药理学上可行的分子。我们的中心假设是，围绕 HF600 的命中引导优化将产生用于心力衰竭药物治疗的新候选治疗药物。将实现三个具体目标本项目旨在检验这一假设：（1）在计算机中设计并合成一系列围绕命中分子 HF600 构建的药理学上可行的 SERCA 激活剂； (2) 功能评价 SERCA 激活剂的原位活性以及在人 iPSC 心肌细胞和动物来源的成人心室中的活性肌细胞； (3) 确定 SERCA 激活剂的治疗效果、安全性和药代动力学。小分子候选物的治疗效果将使用患病的 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进行评估研究。我们现在拥有大量初步数据，表明我们围绕 HF600 构建了一种新的 SERCA 激活器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的影响明显的长期心脏毒性。这个出色的初步数据为激活 SERCA 进行 HF 治疗。我们杰出的多学科团队和高度互补的方法基于经过验证的药理学靶标，确保成功发现新的药理学候选药物心力衰竭患者的治疗。