Drug-like small molecule modulators of the Integrated Stress Response

综合应激反应的类药物小分子调节剂

基本信息

批准号：
7263952
负责人：
DAVID RON
金额：
$ 33.64万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-20 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7263952
关键词：
Active Sites Affect Aging Allosteric Site Amino Acids Antibodies Antibody Formation Apical Arts Binding Biochemical Process Biological Assay Biological Availability Biological Response Modifier Therapy Catalytic Domain Cell Survival Cells Cessation of life Client Complex Computing Methodologies Condition Cultured Cells Data Diabetes Mellitus Disease Docking Endoplasmic Reticulum Environment Enzymatic Biochemistry Enzymes Equilibrium Event Exhibits Failure Fluorescence Resonance Energy Transfer Functional disorder Future Genetic Glucokinase Glycogen storage disease type II Goals Homeostasis Human In Vitro Knock-out Lead Ligands Lysosomal Storage Diseases Lysosomes Mediating Modeling Molecular Chaperones Molecular Weight Neurodegenerative Disorders Numbers Organ Organelles Organic Chemistry PERK kinase Parkinson Disease Pathway interactions Peptide Initiation Factors Pharmaceutical Preparations Pharmacy (field)Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physicians Production Protein Biosynthesis Protein Dephosphorylation Proteins Quality Control Recombinant Proteins Recruitment Activity Relaxation Research Personnel Role Serine Signal Transduction Signal Transduction Pathway Site Sorting - Cell Movement Specificity Starvation Stereotyping Stream Stress Surface System Testing Therapeutic Upper arm Virtual Library antibody conjugate attenuation base biological adaptation to stress cell type clinically relevant coping cost desire disease-causing mutation enzyme replacement therapy gene function high throughput screening human disease improved in vitro Assay inhibitor/antagonist loss of function mutant phosphatase inhibitor programs protein folding protein misfolding response small molecule success tool trafficking

项目摘要

DESCRIPTION (provided by applicant): Protein misfolding in the early secretory pathway exerts it pathological affects by two distinct mechanisms: Retention and degradation of misfolded mutant proteins by the endoplasmic reticulum's (ER) quality control machinery leads to loss-of-function phenotypes (exemplified by lysosomal storage diseases). Production and accumulation of the misfolded protein threatens the integrity of the organelle by causing ER stress, leading to cell dysfunction and death, which is believed to contribute to neurodegenerative disorders, diabetes mellitus and other diseases of aging. The protein folding environment in the ER is controlled by a small number of signal transduction pathways and these respond to ER stress in a stereotyped fashion, mediating the unfolded protein response (UPR). Recent evidence suggests that the level of signaling in the UPR is defined by global parameters and by the averaged needs of the ER's diverse protein clientele. It is unlikely therefore that the UPR is finely tuned to the specific exigencies of any one mutation-causing disease. Evidence for this has recently presented itself as circumstances in which knockout of normal genes that function in the UPR improved survival under conditions of ER stress. Such examples of failure of homeostasis indicate that the UPR can be manipulated therapeutically in pathophysiological conditions. Regulated phosphorylation and dephosphorylation of translation initiation factor 2a (elF2a) is a well understood and potentially malleable arm of the UPR, referred to as the integrated stress response (ISR). We propose to identify drug like small molecules that will enhance and others that will reduce the ISR's activity. Transient inhibition of the ISR might overwhelm the quality control mechanism of the ER and promote trafficking of enzymatically active mutant proteins to their functional compartment, alleviating the associated loss of function phenotypes. ISR inactivation might also prove beneficial in the cell culture based production of biotherapeutics used to treat diseases caused by misfolding by enzyme replacement therapy. Activators of the ISR are likely to protect cells and organs against the lethal consequences of ER stress and may prove useful in treating diseases of aging. To accomplish these goals we will develop high throughput screens (HTS) for compounds that inhibit the ER stress inducible elF2a kinase PERK and secondary screens to evaluate the potency, specificity, bioavailability and off-target effects of the compounds. In a parallel strand we will develop HTS assays for inhibitors of elF2a dephosphorylation and others for activators of elF2a kinases, which function by non-canonical mechanisms and activate the ISR without causing stress. The long-term goal of this proposal is therefore to create a pharmacological platform for manipulating the cellular response to misfolded proteins. Given the pervasive role of protein misfolding in human diseases, such agents are likely to become part of the therapeutic armamentarium of future physicians.

描述（由申请人提供）：早期分泌途径中的蛋白质错误折叠会通过两种不同的机制发挥病理影响：内质网（ER）的质量控制机制的保留和降解错误折叠突变蛋白的质量控制机制损失了功能型（exemplied）由溶酶体储存疾病）。错误折叠蛋白的生产和积累通过引起ER压力而导致细胞功能障碍和死亡威胁到细胞器的完整性，这被认为会导致神经退行性疾病，糖尿病，糖尿病和其他衰老疾病。 ER中的蛋白质折叠环境受到少量信号转导途径的控制，并且以定型的方式对ER应力做出反应，从而介导了展开的蛋白质反应（UPR）。最近的证据表明，UPR中的信号传导水平是由全球参数以及ER多种蛋白质客户群的平均需求定义的。因此，不可能将UPR细微地调整为任何一种引起突变疾病的特定紧急情况。最近的证据表明，在ER应激条件下，在UPR中起作用的正常基因的敲除可以提高生存率的情况。这种体内平衡失败的例子表明，在病理生理条件下可以对UPR进行治疗。翻译起始因子2a（ELF2A）的调节磷酸化和去磷酸化是UPR的一个充分理解且可能具有延展性的臂，称为综合应力响应（ISR）。我们建议鉴定出像小分子一样可以增强的药物，而其他将减少ISR活性的药物。 ISR的瞬态抑制可能会淹没ER的质量控制机制，并促进酶活性突变蛋白的运输到其功能区室，从而减轻相关的功能表型损失。 ISR灭活也可能证明对基于细胞培养的生物疗法的产生，用于治疗酶替代疗法的折叠率错误引起的疾病。 ISR的激活剂可能会保护细胞和器官免受ER应激的致命后果，并可能在治疗衰老疾病中有用。为了实现这些目标，我们将针对抑制ER应力诱导的ELF2A激酶PERK和二级筛选的化合物开发高吞吐量筛选（HTS），以评估化合物的效能，特异性，生物利用度和非目标效应。在平行线中，我们将开发HTS测定ELF2A脱磷酸化和其他ELF2A激酶激活剂的HTS测定法，该激活剂通过非经典机制起作用并激活ISR而不会引起应力。因此，该提案的长期目标是创建一个药理平台，以操纵对错误折叠蛋白的细胞反应。鉴于蛋白质错误折叠在人类疾病中的普遍作用，此类药物很可能成为未来医生治疗的武器库的一部分。