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Mechanism and Synergy of gamma-Secretase Modulators

γ-分泌酶调节剂的机制和协同作用

基本信息

批准号：
9270085
负责人：
YUEMING LI
金额：
$ 42.85万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9270085
关键词：
Abeta synthesis Acetic Acids Acids Active Sites Alzheimer&apos s Disease Amyloid beta-Protein Amyloid beta-Protein Precursor Animal Model Animals Binding Binding Sites Biochemical Biological Assay Brain Catalytic Domain Categories Cell model Cells Characteristics Cleaved cell Clinical Research Clinical Trials Cognition Combined Modality Therapy Complex Cryoelectron Microscopy Crystallization Development Disease Drug Targeting Enzymes Exhibits Generations Human Imidazole Label Lead Learning Maps Memory Molecular Molecular Conformation Mutagenesis Natural Products Non-Steroidal Anti-Inflammatory Agents Pathogenicity Pathologic Peptides Pharmaceutical Preparations Photoaffinity Labels Physiological Play Production Reporting Research Role Safety Shapes Signal Transduction Site Structural Models Structure Synaptic plasticity Testing Therapeutic Variant Work amyloid pathology amyloid precursor protein processing base clinical candidate clinical development clinical investigation crosslink design drug development effective therapy gamma secretase improved inhibitor/antagonist insight mouse model next generation notch protein novel novel therapeutic intervention pre-clinical presenilin public health relevance small molecule synergism

项目摘要

DESCRIPTION (provided by applicant): The overall objectives of this proposal are to elucidate the mechanism of action of different classes of next generation γ-secretase modulators (GSMs), to determine their synergistic effect, and to apply them in examining the role of Aβ42, Aβ38 and Aβ37 in amyloid pathology, synaptic plasticity and learning and memory. The development of GSMs that suppress γ-secretase activity for Aβ42 production and yet do not affect overall APP processing and cleavages of other substrates has emerged as a promising strategy for AD therapy. Progress in the development of these clinical candidates depends on a deeper understanding of the drug-target interactions. To this end we propose to map the binding site of acid GSMs within the γ-secretase complex and to investigate the structural basis of γ-secretase modulation. Additionally, we will determine the mechanism of cooperatively between the γ-secretase active site and the imidazole based GSM binding site(s). Finally, we will examine the synergistic effect of two classes of GSMs in cellular and animal models with a focus on safety, synaptic plasticity and learning and memory. The proposed research will provide mechanistic insights into GSM modulation of γ-secretase, the function of Aβ in disease and new therapeutic strategies, shaping our understanding of GSM selectivity and advancing our ability to design effective treatment.

描述（由申请人提供）：本提案的总体目标是阐明不同类别的下一代γ-分泌酶调节剂（GSM）的作用机制，确定其协同效应，并将其应用于检查Aβ42、Aβ38和Aβ37在淀粉样蛋白病理学、突触可塑性以及学习和记忆中的作用。抑制 Aβ42 产生的 γ 分泌酶活性但不影响整体 APP 加工和其他底物裂解的 GSM 的开发已成为 AD 治疗的一种有前途的策略。这些临床候选药物的开发进展取决于对药物与靶标相互作用的更深入了解。为此，我们建议绘制 γ-分泌酶复合物内酸性 GSM 的结合位点图，并研究 γ-分泌酶调节的结构基础。此外，我们将确定 γ-分泌酶活性位点和基于咪唑的 GSM 结合位点之间的协同机制。最后，我们将研究两类 GSM 在细胞和动物模型中的协同效应，重点关注安全性、突触可塑性以及学习和记忆。拟议的研究将为 γ-分泌酶的 GSM 调节、Aβ 在疾病中的功能和新的治疗策略提供机制见解，形成我们对 GSM 选择性的理解并提高我们设计有效治疗的能力。