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

• 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
• 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' 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

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 阿尔茨海默病（AD）是最普遍的痴呆症，目前尚无有效的疾病改善疗法。我们 最近的研究已经将赖氨酸甲基转移酶G9 a/GLP（也称为EHMT 2/1）的异常与 组蛋白H3赖氨酸9二甲基化（H3 K9 me 2）与AD病理生理学的关系。我们假设药理学 通过小分子抑制G9 a和GLP可以为糖尿病患者提供一种新的有效的治疗策略。 治疗AD。本项目的目的是：（a）证明新发现的G9 a/GLP抑制剂 在AD小鼠模型中有效;（B）将G9 a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。目的1，评估选择性，细胞活性 体外ADME（吸收、分布、代谢和排泄）和体内药代动力学（PK） G9 a/GLP抑制剂的性质;目的2，评价G9 a/GLP抑制剂对 在AD小鼠模型中使行为、突触和转录异常正常化;目标3，优化 目前的G9 a/GLP抑制剂通过设计、合成和测试新的化合物， 以同时优化效力、选择性和PK特性。完成拟议的研究将不会 这不仅验证了我们的治疗假设，而且还产生了一种最终可以转化为 在临床上用于治疗AD。本项目中产生的改进的G9 a/GLP抑制剂也将被 这是评估G9 a/GLP抑制在其他疾病中的治疗潜力的宝贵化学工具。