Targeted Depalmitoylation for the Treatment of NRas-Driven Melanoma

靶向去棕榈酰化治疗 NRas 驱动的黑色素瘤

基本信息

  • 批准号:
    10320690
  • 负责人:
  • 金额:
    $ 12.37万
  • 依托单位:
  • 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:
    2020-09-21 至 2021-08-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Significance: Melanoma is the deadliest form of skin cancer and represents a growing economic burden and health concern in the U.S. While early-stage melanoma can often be treated surgically, therapies for advanced forms of the disease are severely lacking. As rates of melanoma continue to rise, it is imperative that we develop novel and effective treatments for this disease. The most aggressive form of melanoma results from a mutation in the small GTPase NRas and presents in 20% of patients. While NRas is an attractive therapeutic target in melanoma, it has proven notoriously difficult to drug due to the lack of suitable binding pockets on its surface. This limitation has prevented the development of NRas-targeted therapies. Objective: To address the unmet need for NRas-targeted drugs, we will target a previously overlooked region of NRas, the S-palmitoylation of its C-terminal hypervariable region. Numerous studies have confirmed that NRas palmitoylation is required for its cancer signaling activity. To exploit this feature of NRas, we have developed a novel class of Depalmitoylating Molecules (DPALMs) which chemoselectively cleave S-palmitoyl groups from proteins in live cells. Preliminary Data: We have identified a set of DPALM lead compounds which preferentially depalmitoylate NRas in living cells. Furthermore, we found that DPALMs can inhibit downstream Ras signaling pathways and preferentially kill NRas-mutant versus non-NRas-mutant cell lines, highlighting their therapeutic potential. Specific Aims: We will optimize the potency and selectivity of our lead compounds to generate a DPALM suitable for preclinical testing and IND enabling studies. In SPECIFIC AIM 1, we will generate a set of optimized DPALMs using joint synthesis and screening efforts. A modular and robust synthetic strategy will be used to generate new compounds which will then be screened for NRas depalmitoylation activity and selectivity in a validated assay. In SPECIFIC AIM 2, we will evaluate the efficacy of optimized DPALMs in NRas-driven melanoma cell lines. Compounds will be tested for their ability to preferentially inhibit growth and induce cell death in NRas-driven versus control cell lines. The proposed studies will enable the development of a highly NRas-selective DPALM and accelerate the commercialization of this targeted therapy for the treatment of melanoma and several other cancers with high rates of NRas-mutations.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Neal Krishna Devaraj其他文献

Rapid access to phospholipid analogs using thiol-yne chemistry
使用硫醇-炔化学快速获得磷脂类似物
  • DOI:
  • 发表时间:
    2015
  • 期刊:
  • 影响因子:
    8.4
  • 作者:
    Cun Yu Zhou;Haoxing Wu;Neal Krishna Devaraj
  • 通讯作者:
    Neal Krishna Devaraj

Neal Krishna Devaraj的其他文献

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{{ truncateString('Neal Krishna Devaraj', 18)}}的其他基金

Targeted Depalmitoylation for the Treatment of NRas-Driven Melanoma
靶向去棕榈酰化治疗 NRas 驱动的黑色素瘤
  • 批准号:
    10415478
  • 财政年份:
    2022
  • 资助金额:
    $ 12.37万
  • 项目类别:
A Small Molecule Enzyme Replacement for the Treatment of CLN1
用于治疗 CLN1 的小分子酶替代品
  • 批准号:
    10325648
  • 财政年份:
    2021
  • 资助金额:
    $ 12.37万
  • 项目类别:
Illuminating cellular dark matter through the development of novel chemical tools
通过开发新型化学工具照亮细胞暗物质
  • 批准号:
    10437761
  • 财政年份:
    2021
  • 资助金额:
    $ 12.37万
  • 项目类别:
Illuminating cellular dark matter through the development of novel chemical tools
通过开发新型化学工具照亮细胞暗物质
  • 批准号:
    10206532
  • 财政年份:
    2021
  • 资助金额:
    $ 12.37万
  • 项目类别:
Illuminating cellular dark matter through the development of novel chemical tools
通过开发新型化学工具照亮细胞暗物质
  • 批准号:
    10656353
  • 财政年份:
    2021
  • 资助金额:
    $ 12.37万
  • 项目类别:
Illuminating cellular dark matter through the development of novel chemical tools
通过开发新型化学工具照亮细胞暗物质
  • 批准号:
    10581981
  • 财政年份:
    2021
  • 资助金额:
    $ 12.37万
  • 项目类别:
Targeted Depalmitoylation for the Treatment of NRas-Driven Melanoma
靶向去棕榈酰化治疗 NRas 驱动的黑色素瘤
  • 批准号:
    10080443
  • 财政年份:
    2020
  • 资助金额:
    $ 12.37万
  • 项目类别:
Amplifying PET Imaging Signals for In Vivo Detection of Pancreatic Beta-cells
放大 PET 成像信号用于体内检测胰腺 β 细胞
  • 批准号:
    9760875
  • 财政年份:
    2016
  • 资助金额:
    $ 12.37万
  • 项目类别:
Fast in vivo CLICK chemistries for PET imaging
用于 PET 成像的快速体内 CLICK 化学物质
  • 批准号:
    8330484
  • 财政年份:
    2010
  • 资助金额:
    $ 12.37万
  • 项目类别:
Fast in vivo CLICK chemistries for PET imaging
用于 PET 成像的快速体内 CLICK 化学物质
  • 批准号:
    8464101
  • 财政年份:
    2010
  • 资助金额:
    $ 12.37万
  • 项目类别:

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