Computational discovery of SGK1 inhibitors for the treatment of heart disease

用于治疗心脏病的 SGK1 抑制剂的计算发现

基本信息

批准号：
7976659
负责人：
Saumya Das
金额：
$ 21.73万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7976659
关键词：
1-Phosphatidylinositol 3-Kinase Adsorption Adverse effects Angiogenesis Modulating Agents Animal Model Animals Apoptosis Arrhythmia Biological Biological Assay Biomechanics Cardiac Cardiac Myocytes Cardiomyopathies Chemicals Chronic Clinical Computer Assisted Computer Simulation Data Databases Development Disease Engineering Evaluation Fibrosis Fluorescence Polarization Foundations Functional disorder Gene Transfer Genetic Genetic Models Goals Heart Heart Diseases Heart Hypertrophy Heart failure Hypertrophy In Vitro Infarction Inherited Injury Investigation Ischemia Laboratories Lead Ligands Malignant Neoplasms Metabolism Metric Modeling Morbidity - disease rate Mus Myocardial Infarction Pathogenesis Pathology Phenotype Phosphotransferases Physiological Prevalence Process Protein-Serine-Threonine Kinases Reperfusion Injury Reperfusion Therapy Research Personnel Role Sgk protein Signal Transduction Somatic Gene Therapy Specificity Staging Stimulus Stress Structure Structure-Activity Relationship Syndrome Testing Therapeutic Toxic effect Triage Validation Ventricular Arrhythmia Ventricular Dysfunction Work base constriction drug development drug discovery effective therapy gene transfer vector hypertensive heart disease in vitro testing in vivo inhibitor/antagonist innovation kinase inhibitor mortality mouse model novel novel therapeutic intervention outcome forecast public health relevance response small molecule small molecule libraries success therapeutic target tool virtual

项目摘要

DESCRIPTION (provided by applicant): Heart failure (HF) is a clinical syndrome of growing prevalence and is the final common endpoint of a variety of cardiomyopathic processes including myocardial infarction, hypertensive heart disease, and inherited cardiomyopathies. HF is associated with a poor prognosis, with significant mortality attributed to both progressive ventricular dysfunction and lethal ventricular arrhythmias (VA). Hence there is a clear unmet clinical need to develop novel therapies that can ameliorate the development of cardiac dysfunction and fibrosis as well as target lethal arrhythmias. Serum- and glucocorticoid-regulated kinase-1 (SGK1) is a PI3-kinase (PI3K)-dependent kinase that is activated in pathological hypertrophy and HF but not in physiological hypertrophy. Recent work from our laboratory suggests that SGK1 activation contributes to pathological hypertrophy, cardiac fibrosis, and arrhythmia. In contrast, genetic inhibition of SGK1 mitigates heart failure and fibrosis after biomechanical stress and reduces ischemic injury after in vivo cardiac ischemia-reperfusion, but has no effect on baseline cardiac function. On the basis of these data, we propose that pharmacological inhibition of SGK1 would also mitigate adverse remodeling in different models of cardiac pathology, reducing cardiac dysfunction, fibrosis and arrhythmia without having an adverse effect at baseline. Currently there are no specific inhibitors of SGK1 available. We now propose to use an innovative computer aided drug discovery (CADD) platform to identify and optimize small molecule inhibitors of SGK1. In Specific Aim 1, we will use structure- and ligand-based virtual screens of small molecule libraries to identify "hit" compounds that inhibit SGK1 activity. The activity of these compounds will be evaluated using an in vitro fluorescence polarization kinase assay. Importantly, all small molecule "hits" are pre-filtered for optimized ADMET (adsorption, distribution, metabolism, excression and toxicity) metrics, which eliminates compounds/chemotypes that are likely to be triaged in late stage evaluation. In Specific Aim 2, we will further characterize the top candidates for their ability to specifically and effectively inhibit SGK1 in vitro in cardiomyocytes. Using adenoviral gene transfer to create cardiomyocyte validation models in which SGK1 or closely related kinases (Akt1, ILK) are specifically activated or inhibited, the candidate inhibitors will be tested for their specificity and selectivity. Finally, in Specific Aim 3, we will begin to examine the in vivo efficacy and specificity of identified inhibitors using both wildtype mice and unique in vivo mouse models of cardiac SGK1 activation or inhibition. The identification of specific and effective inhibitors for SGK1 would not only provide us with useful tools for our ongoing investigation of SGK1's role in disease pathogenesis but could also provide a small molecule therapeutic lead for strategies treating heart failure and its complications. PUBLIC HEALTH RELEVANCE: Heart failure is a clinical syndrome of growing prevalence and a major cause of morbidity and mortality throughout the world. Hence there is a clear unmet clinical need to develop novel therapies that can ameliorate this important clinical condition. Studies from our group and others using genetically engineered animal models have suggested that inhibition of the kinase, SGK1, could have significant benefits in heart failure and its sequelae. Although there are currently no known pharmacological inhibitors of SGK1, kinases have been considered good targets for drug development in other settings. In this project, we propose to use an innovative computer aided drug discovery approach to identify inhibitors of SGK1. Top candidates will be characterized for their ability to specifically and effectively inhibit SGK1 in isolated heart muscle cells and in hearts of animals. The identification of specific and effective inhibitors for SGK1 would not only yield useful tools for ongoing investigation of disease mechanisms but could also provide a foundation for novel therapeutic approaches to heart failure and its complications.

描述（由申请人提供）：心力衰竭（HF）是一种越来越患病率的临床综合征，是多种心肌病过程的最终常见终点，包括心肌梗塞，高血压心脏病和遗传性心肌病。 HF与预后不良有关，其死亡率显着归因于进行性室性室功能障碍和致命性心律失常（VA）。因此，明确的未满足的临床需要需要开发可改善心脏功能障碍和纤维化的发展以及靶向致命性心律不齐的新疗法。血清和糖皮质激素调节的激酶-1（SGK1）是一种PI3-激酶（PI3K）依赖性激酶，在病理肥大和HF中被激活，但在生理肥大中却没有激活。我们实验室的最新工作表明，SGK1激活有助于病理肥大，心脏纤维化和心律不齐。相反，SGK1的遗传抑制会减轻生物力学应激后的心力衰竭和纤维化，并减少体内心脏缺血再灌注后缺血性损伤，但对基线心脏功能没有影响。根据这些数据，我们建议对SGK1的药理抑制作用也会减轻不同的心脏病理模型中的不良重塑，减少心脏功能障碍，纤维化和心律不齐，而不会在基线时产生不良影响。目前尚无对SGK1的特定抑制剂。现在，我们建议使用创新的计算机辅助药物发现（CADD）平台来识别和优化SGK1的小分子抑制剂。在特定的目标1中，我们将使用小分子库的结构和配体的虚拟筛选来识别抑制SGK1活性的“命中”化合物。这些化合物的活性将使用体外荧光极化激酶测定法评估。重要的是，所有小分子“命中”均已预过滤，以优化ADMET（吸附，分布，代谢，尊重和毒性）指标，该指标消除了可能在晚期评估中可能会进行分类的化合物/化学型。在特定的目标2中，我们将进一步表征顶级候选者的特定有效抑制心肌细胞体外SGK1的能力。使用腺病毒基因转移来创建心肌细胞验证模型，其中SGK1或密切相关的激酶（AKT1，ILK）被专门激活或抑制，将测试候选抑制剂的特异性和选择性。最后，在特定的目标3中，我们将开始使用野生型小鼠和唯一的心脏SGK1激活或抑制体体内小鼠模型来检查鉴定抑制剂的体内功效和特异性。鉴定SGK1的特定和有效抑制剂不仅会为我们提供有用的工具，以持续研究SGK1在疾病发病机理中的作用，而且还可以为治疗心力衰竭及其并发症的策略提供小分子治疗铅。公共卫生相关性：心力衰竭是一种临床综合症的临床综合症，是全球发病率和死亡率的主要原因。因此，有明显的未满足的临床需求来开发可以改善这种重要临床状况的新型疗法。我们小组和其他使用基因工程动物模型的研究表明，抑制激酶SGK1可以在心力衰竭及其后遗症中具有重大益处。尽管目前尚无已知的SGK1药理抑制剂，但激酶被认为是在其他情况下进行药物开发的良好靶标。在这个项目中，我们建议使用创新的计算机辅助药物发现方法来识别SGK1的抑制剂。顶级候选人的特征是其特定有效地抑制孤立心肌细胞和动物心脏中的SGK1的能力。鉴定SGK1的特定和有效抑制剂不仅会产生有用的工具，以持续研究疾病机制，还可以为新颖的心力衰竭治疗方法及其并发症提供基础。