Novel Inhibitors of Lysine Methyltransferases G9a and GLP for the Treatment of Alzheimer's Disease

用于治疗阿尔茨海默病的新型赖氨酸甲基转移酶 G9a 和 GLP 抑制剂

基本信息

批准号：
10752812
负责人：
Jian Jin
金额：
$ 67.85万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10752812
关键词：
Affinity Alzheimer&apos s Disease Assessment tool Behavior Behavioral Binding Biochemical Biological Assay Biological Availability Biophysics Brain Cells ChIP-seq Chemicals Clinic Cognitive Communities Complex Dementia Disease Drug Kinetics Excretory function Functional disorder Gene Expression Genes Genetic Transcription Goals Histone H3 In Vitro Lead Link Lysine Metabolism Methyltransferase Mus Oral Penetration Post-Translational Protein Processing Property Public Health Research Research Personnel Structure Synapses Testing Therapeutic Translating absorption design drug candidate drug metabolism gene repression histone methylation improved in vivo in vivo Model inhibitor mouse model novel novel therapeutic intervention pharmacologic small molecule small molecule inhibitor synaptic function therapeutically effective tool transcriptome sequencing treatment strategy

项目摘要

PROJECT SUMMARY Alzheimer’s disease (AD), the most prevalent dementia, has no effective disease-modifying therapeutics. Our recent studies have linked abnormalities in lysine methyltransferases G9a/GLP (also known as EHMT2/1) and histone H3 lysine 9 dimethylation (H3K9me2) to AD pathophysiology. We hypothesize that pharmacological inhibition of G9a and GLP by small molecules can provide a novel and effective therapeutic strategy for the treatment of AD. The objectives of this project are: (a) to demonstrate that newly-discovered G9a/GLP inhibitors are efficacious in AD mouse models; (b) to optimize small-molecule inhibitors of G9a and GLP into a drug candidate. To achieve these goals, we will pursue three specific aims. Aim 1, assess selectivity, cellular activity and in vitro ADME (absorption, distribution, metabolism and excretion) and in vivo pharmacokinetic (PK) properties of lead G9a/GLP inhibitors; Aim 2, evaluate in vivo effects of lead G9a/GLP inhibitors on normalizing behavioral, synaptic, and transcriptional abnormalities in AD mouse models; Aim 3, Optimize current G9a/GLP inhibitor leads into a drug candidate by designing, synthesizing and testing novel compounds to simultaneously optimize potency, selectivity and PK properties. Completion of the proposed studies will not only validate our therapeutic hypothesis, but also generate a drug candidate that could be ultimately translated in the clinic for the treatment of AD. The improved G9a/GLP inhibitors generated in this project will also be invaluable chemical tools for assessing the therapeutic potential of G9a/GLP inhibition in other diseases.

项目摘要阿尔茨海默氏病（AD）是最普遍的痴呆症，没有有效的疾病改良疗法。我们的最近的研究已将赖氨酸甲基转移酶G9A/GLP（也称为EHMT2/1）和组蛋白H3赖氨酸9二甲基化（H3K9ME2）至AD病理生理学。我们假设该药物小分子抑制G9a和GLP可以为该策略提供新颖而有效的治疗策略 AD的处理。该项目的目标是：（a）证明新发现的G9A/GLP抑制剂在AD鼠标模型中有效；（b）将G9A和GLP的小分子抑制剂优化为药物候选人。为了实现这些目标，我们将追求三个具体目标。目标1，评估选择性，细胞活性和体外ADME（吸收，分布，代谢和排泄）和体内药代动力学（PK）铅G9A/GLP抑制剂的特性； AIM 2，评估铅G9A/GLP抑制剂对体内影响在AD小鼠模型中标准化行为，突触和转录异常； AIM 3，优化当前的G9A/GLP抑制剂通过设计，合成和测试新颖化合物导致候选药物简单地优化效力，选择性和PK属性。拟议研究的完成将不会仅验证我们的治疗假设，但也会产生一个可以最终翻译的药物在AD治疗的诊所中。该项目中产生的改进的G9A/GLP抑制剂也将是评估其他疾病中G9A/GLP抑制的治疗潜力的宝贵化学工具。