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

项目总结 阿尔茨海默病(AD)是最常见的痴呆症，目前还没有有效的疾病修饰疗法。我们的 最近的研究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)对AD的病理生理作用。我们假设从药理上讲 小分子抑制G9a和GLP可为临床提供一种新的有效的治疗策略 治疗阿尔茨海默病。该项目的目标是：(A)证明新发现的G9a/GLP抑制剂 在AD小鼠模型中有效；(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 体外ADME(吸收、分布、代谢和排泄)和体内药代动力学(PK) G9a/GLP铅抑制剂的性质；目的2，评价G9a/GLP铅抑制剂的体内效应 使AD小鼠模型的行为、突触和转录异常正常化；目标3，优化 目前的G9a/GLP抑制剂通过设计、合成和测试新化合物而成为候选药物 以同时优化效力、选择性和PK属性。建议的研究将不会完成 不仅验证了我们的治疗假说，而且还产生了一种最终可以翻译的候选药物 在治疗阿尔茨海默病的诊所。在该项目中产生的改进的G9a/GLP抑制剂也将是 评估G9a/GLP抑制在其他疾病中的治疗潜力的宝贵化学工具。

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.