Prevention of Cardiac Cell Death by Mst1 inhibitor

Mst1 抑制剂预防心肌细胞死亡

• 批准号: 7815345
• 负责人: Junichi Sadoshima
• 金额: $ 55.12万
• 依托单位: VASADE BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7815345
• 关键词: Acute; Apoptosis; Biological Assay; Cardiac; Cardiac Myocytes; Cell Death; Cells; Cessation of life; Clinical; Clinical Treatment; Congestive Heart Failure; Development; Development Plans; Dominant-Negative Mutation; Doxorubicin; Event; Family suidae; Future; Goals; Grant; Heart; Heart failure; Histones; Hypertrophy; Injury; Intervention; Investigation; Ischemia; Knowledge; LATS2 gene; Lead; Left; Left Ventricular Dysfunction; Legal patent; Marketing; Mechanics; Mediating; Medicine; Methods; Modeling; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Pathogenesis; Patients; Peptides; Phase; Phosphotransferases; Play; Prevention; Property; Reperfusion Injury; Reperfusion Therapy; Role; Small Business Technology Transfer Research; Sterility; Stress; Structure-Activity Relationship; Transgenic Mice; United States National Institutes of Health; Ventricular; abstracting; base; caspase-3; improved; in vivo; inhibitor/antagonist; mimetics; mitochondrial dysfunction; myocardial infarct sizing; novel; overexpression; phase 2 study; preclinical study; prevent; public health relevance; response; small molecule

DESCRIPTION (provided by applicant): 6. Abstract Almost 20 million people suffer from ischemic heart diseases in US and one million patients develop myocardial infarction (MI) every year. Many patients develop heart failure even if they survive the acute event, which clearly indicates that current interventions are not sufficient. Thus, the development of a new class of medicine, which prevents ischemia/reperfusion (I /R) injury, would have a large market opportunity and significant clinical advance. Cardiac myocyte death, including apoptosis, is intimately involved in the pathogenesis of heart failure. Mammalian sterile 20 like kinase 1 (Mst1) plays an important role in mediating cardiac myocyte apoptosis and is intimately involved in the pathogenesis of congestive heart failure (Vasade, US patent 7160859, 2007). Using transgenic mice with cardiac specific overexpression of dominant negative Mst1 (Tg-DN-Mst1), inhibition of endogenous Mst1 suppresses cardiac myocyte apoptosis in response to I/R, thereby reducing the size of MI and improving long-term cardiac function. One of the long-term goals of Vasade is to develop Mst1 specific inhibitors for the treatment of I/R injury. Through our effort made possible by the phase I STTR grant from NIH, Vasade 1) has discovered a novel and specific peptide Mst1 inhibitor (termed Mst1 inhibitory peptide 120 (MIP120)) and made it cell permeable (termed TAT120) and 2) has established an ELISA-based high throughput method to accurately determine the kinase activity of Mst1. To our knowledge, MIP120 and TAT120 are the only compounds currently available inhibiting the kinase activity of Mst1. In the phase II STTR project, Vasade will provide unequivocal evidence showing that the Mst1 inhibitor is useful for the prevention of cardiac myocyte death by I/R in vivo and identify a refined lead compound for the development of peptide mimetic Mst1 inhibitors for treatment of I/R injury. Specific aims are: Aim 1 To determine the effect of TAT120 on the size of MI and cardiac myocyte apoptosis in response to I/R in vivo, thereby establishing the proof of concept for the use of Mst1 inhibitors to reduce I/R injury using the mouse and pig models of ischemia/reperfusion. Aim 2 To further improve the property of MIP120 /TAT120 as Mst1 inhibitors and to elucidate the structure- function relationship of MIP120/TAT120 for the development of better peptides or peptide mimetics This phase II study will provide strong proof of concept and refined lead compounds, which will be used for the development of peptide mimetic small molecule Mst1 inhibitors for the future clinical treatment of I/R injury in the heart. PUBLIC HEALTH RELEVANCE: Almost 20 million people suffer from ischemic heart diseases in US and one million patients develop myocardial infarction (MI) every year. Many patients develop heart failure even if they survive the acute event, which clearly indicates that current interventions are not sufficient to prevent myocardial cell death and resultant left ventricular (LV) dysfunction. The current investigation is aiming at generating a new class of medicine preventing ischemia/reperfusion (I /R) injury, which should have a large market opportunity and significant clinical importance.

描述（由申请人提供）：6。摘要美国每年有近2000万人患有缺血性心脏病，其中100万人发生心肌梗死。许多患者即使在急性事件中存活下来也会发生心力衰竭，这清楚地表明目前的干预措施是不够的。因此，开发一类新的药物，防止缺血/再灌注（I /R）损伤，将有很大的市场机会和显着的临床进展。心肌细胞死亡，包括凋亡，是密切参与心力衰竭的发病机制。哺乳动物无菌20样激酶1（Mst 1）在介导心肌细胞凋亡中起重要作用，并且与充血性心力衰竭的发病机制密切相关（Vasade，美国专利7160859，2007）。使用心脏特异性过表达显性负性Mst 1（Tg-DN-Mst 1）的转基因小鼠，抑制内源性Mst 1可抑制I/R引起的心肌细胞凋亡，从而减少MI的大小并改善长期心脏功能。Vasade的长期目标之一是开发用于治疗I/R损伤的Mst 1特异性抑制剂。通过我们的努力，由NIH的I期STTR资助，Vasade 1）发现了一种新的和特异性的肽Mst 1抑制剂（称为Mst 1抑制肽120（MIP 120）），并使其具有细胞渗透性（称为TAT 120），2）建立了一种基于ELISA的高通量方法，以准确测定Mst 1的激酶活性。据我们所知，MIP 120和TAT 120是目前唯一可用的抑制Mst 1激酶活性的化合物。在II期STTR项目中，Vasade将提供明确的证据，表明Mst 1抑制剂可用于预防体内I/R引起的心肌细胞死亡，并确定一种精制的先导化合物，用于开发肽模拟Mst 1抑制剂，用于治疗I/R损伤。具体目标是：目的1利用小鼠和猪心肌缺血/再灌注模型，研究TAT 120对心肌缺血再灌注损伤的影响，为Mst 1抑制剂减轻心肌缺血再灌注损伤提供理论依据。目的2进一步提高MIP 120/TAT 120作为Mst 1抑制剂的性能，阐明MIP 120/TAT 120的结构-功能关系，为开发更好的肽或肽模拟物提供有力的概念验证和精制先导化合物。其将用于开发肽模拟物小分子Mst 1抑制剂，用于心脏I/R损伤的未来临床治疗。 公共卫生关系：在美国，每年约有2000万人患有缺血性心脏病，其中有100万患者发生心肌梗死（MI）。许多患者即使在急性事件中存活也会发生心力衰竭，这清楚地表明目前的干预措施不足以预防心肌细胞死亡和由此产生的左心室（LV）功能障碍。目前的研究旨在产生一类新的预防缺血/再灌注（I /R）损伤的药物，这将具有很大的市场机会和重要的临床意义。