Novel Antagonists of the N-terminal Domain of the CRF Receptor Type 1 for Alzheimer's Disease

治疗阿尔茨海默病的 1 型 CRF 受体 N 末端结构域的新型拮抗剂

基本信息

批准号：
10433769
负责人：
Robert A Rissman
金额：
$ 35.45万
依托单位：
VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10433769
关键词：
AD transgenic mice Academia Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Amyloid beta-Protein Animal Model Animals Area Award Benchmarking Binding Biological Assay Biotin Brain C-terminal CRF receptor type 1 Cells Chemicals Clinical Trials Collaborations Corticotropin-Releasing Hormone Receptors Critical Pathways Development Disease Progression Extracellular Domain Fluorescence Resonance Energy Transfer Freezing Funding Generations Genomics Hippocampus (Brain)Hormones Hypothalamic structure Impaired cognition In Vitro Institutes Label Lead Libraries Ligand Binding Measures Mediating Mediator of activation protein Medical Membrane Mus N-terminal Neuropeptides Parents Pathology Penetrance Pharmaceutical Chemistry Pharmacologic Substance Research Risk Factors Rodent Senile Plaques Signal Transduction Slice Specificity Stress Structure-Activity Relationship Testing Tissues Toxic effect Up-Regulation Validation Work antagonist base beta amyloid pathology brain tissue efficacy study experimental study high throughput screening in vivo lead optimization maltose-binding protein molecular modeling mouse model neurochemistry neuropathology novel pharmacokinetics and pharmacodynamics radioligand receptor scaffold scale up small molecule tau Proteins tau phosphorylation

项目摘要

Project Summary/Abstract CRF is the major neuropeptide hormone associated with stress and is mediated predominantly signaling through CRF receptor subtype 1 (CRFR1) in the CNS. CRF signaling has been implicated in Alzheimer’s disease (AD) as there is increased CRF expression, CRF binding to and upregulation of CRFR1 receptors in the cortex, hippocampus and hypothalamus appears to occur early in disease AD progression and are prominent neurochemical changes in areas vulnerable to AD neuropathology. CRFR1 expression also intersects with Abeta (Aβ) and tau pathologies, both known to be critical hallmarks of AD. There have been substantial efforts in academia and pharmaceutical companies to develop potent small molecule antagonists of CRFR1, however, even the current 3rd generation antagonists are still directed against the C- terminal regions of the CRFR1 receptor are still based on the 2nd generation chemical scaffolds along with their inherent toxicity liabilities. This project capitalizes on the molecular model of CRFR1 activation, established through extensive studies, where the first step is binding of CRF to specific ligand binding motifs in the receptor’s N-terminal region and binding motifs. We have developed and validated an novel homogeneous TR-FRET assay to measure the direct binding of biotin-labeled CRF to the N-terminal extracellular domain (ECD) of maltose binding protein labeled CRFR1 compatible with very high-throughput screening. We have developed this assay, verified that unlabeled CRF displaces biotin-CRF, and that several known C-terminal CRFR1 antagonists do not displace CRF from the N-term CRFR1 ECD. Motivated by these recent experiments, we propose to screen a large library of compounds against N-terminal CRFR1 ECD in collaboration with the Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute. In Aim 1, we will fully implement this primary N- terminal CRFR1 ECD assay and complete an HTS campaign to identify and confirm candidate N-terminal CRFR1 antagonists. Aim 2 will validate these hits for potency, specificity, functional antagonism and elucidate emergent structure activity relationships (SAR) to assess their chemical tractability. Aim 3 will advance validated hits through hit-to-lead through cycles of medicinal chemistry and testing through 2° critical path assays for potency and functional antagonism, then additional lead optimization cycles where additionally, potency and efficacy in biologically relevant 3° assays for target engagement (e.g. brain tissue slices). The best 2-3 probe compound(s), will be scale-up to benchmark their ADME/T, PK/PD and brain penetrance and in vivo proof-of-concept studies in mouse AD models.

项目概要/摘要 CRF 是与压力相关的主要神经肽激素，主要介导信号传导通过中枢神经系统中的 CRF 受体亚型 1 (CRFR1)，CRF 信号传导与阿尔茨海默病有关。疾病（AD），因为 CRF 表达增加，CRF 与 CRFR1 受体的结合和上调皮质、海马和下丘脑似乎出现在 AD 疾病进展的早期，并且易受 AD 神经病理学影响的区域也出现显着的神经化学变化。与 Abeta (Aβ) 和 tau 病理学相交叉，这两者都是 AD 的关键标志。学术界和制药公司付出巨大努力来开发有效的小分子拮抗剂然而，CRFR1，即使是目前的第三代拮抗剂仍然针对C端区域 CRFR1受体的研究仍然基于第二代化学支架及其固有的毒性该项目利用了通过广泛建立的 CRFR1 激活的分子模型。研究中，第一步是将 CRF 与受体 N 末端的特定配体结合基序结合我们开发并验证了一种新型同质 TR-FRET 测定法。测量生物素标记的 CRF 与麦芽糖 N 末端胞外结构域 (ECD) 的直接结合我们开发了这种结合蛋白标记的 CRFR1，与非常高通量的筛选兼容。测定，证实未标记的 CRF 取代了生物素-CRF，并且几个已知的 C 末端 CRFR1 拮抗剂不会取代 N 端 CRFR1 ECD 中的 CRF。受这些最近实验的启发，我们。提议与 N 端 CRFR1 ECD 合作筛选大型化合物库桑福德伯纳姆普雷比斯医学发现研究所的康拉德普雷比斯化学基因组学中心。在目标 1 中，我们将全面实施该主要 N 末端 CRFR1 ECD 检测并完成 HTS 活动识别并确认候选 N 端 CRFR1 拮抗剂，目标 2 将验证这些命中的效力，特异性、功能拮抗作用并阐明紧急结构活动关系（SAR）以评估其目标 3 将通过药物循环推进经过验证的命中。通过 2° 关键路径测定进行化学和测试以测定效力和功能拮抗作用，然后进行额外的领先的优化周期，此外，针对目标的生物学相关 3° 测定中的效力和功效最好的 2-3 种探针化合物将被放大以对其进行基准测试。 ADME/T、PK/PD 和脑外显率以及小鼠 AD 模型的体内概念验证研究。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

An extra X chromosome among adult women in the Million Veteran Program: A more benign perspective of trisomy X.

百万退伍军人计划中成年女性的额外 X 染色体：X 三体性的更良性视角。

DOI：
发表时间：
2024-03-05
期刊：
影响因子：
0
作者：
Davis, Shanlee M;Teerlink, Craig C;Lynch, Julie A;Klamut, Natalia;Gorman, Bryan R;Pagadala, Meghana S;Panizzon, Matthew S;Merritt, Victoria C;Genovese, Giulio;Ross, Judith L;Hauger, Richard L
通讯作者：
Hauger, Richard L