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:
  • 金额:
    $ 67.85万
  • 依托单位:
  • 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

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.
项目总结

项目成果

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Jian Jin其他文献

Jian Jin的其他文献

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{{ truncateString('Jian Jin', 18)}}的其他基金

Dissecting and targeting canonical and non-canonical oncogenic functions of EZH2 in cancer
剖析和靶向 EZH2 在癌症中的典型和非典型致癌功能
  • 批准号:
    10544005
  • 财政年份:
    2022
  • 资助金额:
    $ 67.85万
  • 项目类别:
Dissecting and targeting canonical and non-canonical oncogenic functions of EZH2 in cancer
剖析和靶向 EZH2 在癌症中的典型和非典型致癌功能
  • 批准号:
    10389877
  • 财政年份:
    2022
  • 资助金额:
    $ 67.85万
  • 项目类别:
Dissecting and targeting canonical and non-canonical oncogenic functions of EZH2 in caner
剖析和靶向 EZH2 在癌症中的典型和非典型致癌功能
  • 批准号:
    10908135
  • 财政年份:
    2022
  • 资助金额:
    $ 67.85万
  • 项目类别:
Discovery of First-in-class WDR5 PROTACs as a Novel Therapeutic Strategy for MLL-rearranged Leukemias
发现一流的 WDR5 PROTAC 作为 MLL 重排白血病的新型治疗策略
  • 批准号:
    10712396
  • 财政年份:
    2022
  • 资助金额:
    $ 67.85万
  • 项目类别:
Discovery of First-in-class WDR5 PROTACs as a Novel Therapeutic Strategy for MLL-rearranged Leukemias
发现一流的 WDR5 PROTAC 作为 MLL 重排白血病的新型治疗策略
  • 批准号:
    10387368
  • 财政年份:
    2022
  • 资助金额:
    $ 67.85万
  • 项目类别:
Discovery of First-in-class WDR5 PROTACs as a Novel Therapeutic Strategy for MLL-rearranged Leukemias
发现一流的 WDR5 PROTAC 作为 MLL 重排白血病的新型治疗策略
  • 批准号:
    10615610
  • 财政年份:
    2022
  • 资助金额:
    $ 67.85万
  • 项目类别:
Discovery of First-in-class WDR5 PROTACs as a Novel Therapeutic Strategy for MLL-rearranged Leukemias
发现一流的 WDR5 PROTAC 作为 MLL 重排白血病的新型治疗策略
  • 批准号:
    10745902
  • 财政年份:
    2022
  • 资助金额:
    $ 67.85万
  • 项目类别:
Development of Novel PROTACs Targeting the ENL YEATS Domain for Treating MLL-rearranged Leukemias
开发针对 ENL YEATS 结构域的新型 PROTAC,用于治疗 MLL 重排白血病
  • 批准号:
    10222062
  • 财政年份:
    2021
  • 资助金额:
    $ 67.85万
  • 项目类别:
Development of Novel PROTACs Targeting the ENL YEATS Domain for Treating MLL-rearranged Leukemias
开发针对 ENL YEATS 结构域的新型 PROTAC,用于治疗 MLL 重排白血病
  • 批准号:
    10372195
  • 财政年份:
    2021
  • 资助金额:
    $ 67.85万
  • 项目类别:
Development of Novel PROTACs Targeting the ENL YEATS Domain for Treating MLL-rearranged Leukemias
开发针对 ENL YEATS 结构域的新型 PROTAC,用于治疗 MLL 重排白血病
  • 批准号:
    10616478
  • 财政年份:
    2021
  • 资助金额:
    $ 67.85万
  • 项目类别:
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