Development of covalent PIP4K2 inhibitors for the treatment of p53 deficient lung tumors

开发共价 PIP4K2 抑制剂用于治疗 p53 缺陷型肺部肿瘤

基本信息

  • 批准号:
    8942703
  • 负责人:
  • 金额:
    $ 54.09万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-05-07 至 2020-04-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Loss or mutations in the tumor suppressor gene TP53 (encoding p53) is one of the most frequent events in cancer. Clinical and functional studies have unequivocally validated the functional importance of the loss of p53 in cancer but unfortunately there are no small molecule approaches to address this challenge. Our labs have recently demonstrated that the kinase activity of type 2 phosphatidylinositol-5-phosphate 4-kinase A and B (PIP4K2A and B) encoded by PIP4K2A and PIP4K2B genes are crucial for the growth of cancers that harbor TP53 deletions. Specifically we have demonstrated that germ line deletion of PIP4K2A and PIP4K2B in mice suppresses tumor formation in the context of TP53 deletion and that prototype inhibitors selectively kill cells harboring TP53 deletions. The goal of this proposal is to develop the first covalent PIP4K2 inhibitors with the requisite potency, selectivity and pharmacological properties to interrogate the potential of PIP4K2 as a therapeutic target in lung cancer and other diseases characterized by loss of p53 function and high level of PIP4K2s. We have developed a prototype covalent PIP4K2 inhibitor, THZ-2-72-1, which irreversibly targets PIP4K2 and selectively inhibits the proliferation of p53 deficient lung cancer cell lines. We will use a focused medicinal chemistry approach informed by modeling and co-crystal structures to develop optimized inhibitors that can be tested using xenograft, genetically engineered and primagraft models for their ability to inhibit TP53-deficient tumor growth. These studies will serve to pharmacologically validate PIP4K2 as a new target and will provide prototype drugs that can be further optimized for eventual clinical testing.
 描述(由申请人提供):肿瘤抑制基因TP 53(编码p53)的缺失或突变是癌症中最常见的事件之一。临床和功能研究已经明确证实了癌症中p53缺失的功能重要性,但不幸的是,没有小分子方法来解决这一挑战。我们的实验室最近已经证明,由PIP 4 K2 A和PIP 4 K2 B基因编码的2型磷脂酰肌醇-5-磷酸4-激酶A和B(PIP 4 K2 A和B)的激酶活性对于具有TP 53缺失的癌症的生长至关重要。具体地,我们已经证明,小鼠中PIP 4K 2A和PIP 4K 2B的生殖系缺失在TP 53缺失的情况下抑制肿瘤形成,并且原型抑制剂选择性地杀死携带TP 53缺失的细胞。的目标 该建议是开发第一种具有必需的效力、选择性和药理学性质的共价PIP 4K 2抑制剂,以研究PIP 4K 2作为肺癌和其它以p53功能丧失和高水平PIP 4K 2为特征的疾病的治疗靶点的潜力。我们已经开发了一种原型共价PIP 4K 2抑制剂THZ-2-72-1,其不可逆地靶向PIP 4K 2并选择性地抑制p53缺陷型肺癌细胞系的增殖。 我们将使用一种集中的药物化学方法,通过建模和共晶体结构来开发优化的抑制剂,这些抑制剂可以使用异种移植,基因工程和primagraft模型来测试其抑制TP 53缺陷肿瘤生长的能力。这些研究将有助于验证PIP 4K 2作为新靶点的可行性,并将提供原型药物,这些药物可以进一步优化以用于最终的临床测试。

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(2)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

NATHANAEL Schiander GRAY其他文献

NATHANAEL Schiander GRAY的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('NATHANAEL Schiander GRAY', 18)}}的其他基金

Targeting CDK7 in CCNE1-amplified Ovarian Cancer
CCNE1 扩增的卵巢癌中靶向 CDK7
  • 批准号:
    10367792
  • 财政年份:
    2022
  • 资助金额:
    $ 54.09万
  • 项目类别:
Targeting CDK7 in CCNE1-amplified Ovarian Cancer
CCNE1 扩增的卵巢癌中靶向 CDK7
  • 批准号:
    10576332
  • 财政年份:
    2022
  • 资助金额:
    $ 54.09万
  • 项目类别:
Small molecule-induced degradation of dengue proteins as an antiviral strategy
小分子诱导的登革热蛋白降解作为抗病毒策略
  • 批准号:
    10472071
  • 财政年份:
    2020
  • 资助金额:
    $ 54.09万
  • 项目类别:
Small molecule-induced degradation of dengue proteins as an antiviral strategy
小分子诱导的登革热蛋白降解作为抗病毒策略
  • 批准号:
    10052821
  • 财政年份:
    2020
  • 资助金额:
    $ 54.09万
  • 项目类别:
Validating the Flavivirus Envelope Protein as an Antiviral Target
验证黄病毒包膜蛋白作为抗病毒靶点
  • 批准号:
    10338189
  • 财政年份:
    2020
  • 资助金额:
    $ 54.09万
  • 项目类别:
Validating the Flavivirus Envelope Protein as an Antiviral Target
验证黄病毒包膜蛋白作为抗病毒靶点
  • 批准号:
    10578759
  • 财政年份:
    2020
  • 资助金额:
    $ 54.09万
  • 项目类别:
Validating the Flavivirus Envelope Protein as an Antiviral Target
验证黄病毒包膜蛋白作为抗病毒靶点
  • 批准号:
    10413666
  • 财政年份:
    2020
  • 资助金额:
    $ 54.09万
  • 项目类别:
Small molecule-induced degradation of dengue proteins as an antiviral strategy
小分子诱导的登革热蛋白降解作为抗病毒策略
  • 批准号:
    10661608
  • 财政年份:
    2020
  • 资助金额:
    $ 54.09万
  • 项目类别:
Small molecule-induced degradation of dengue proteins as an antiviral strategy
小分子诱导的登革热蛋白降解作为抗病毒策略
  • 批准号:
    10429876
  • 财政年份:
    2020
  • 资助金额:
    $ 54.09万
  • 项目类别:
Targeting the transcriptional and epigenetic landscape in chemo-refractory Small-Cell Lung Cancer
靶向化疗难治性小细胞肺癌的转录和表观遗传景观
  • 批准号:
    10174856
  • 财政年份:
    2017
  • 资助金额:
    $ 54.09万
  • 项目类别:

相似海外基金

Unraveling the Dynamics of International Accounting: Exploring the Impact of IFRS Adoption on Firms' Financial Reporting and Business Strategies
揭示国际会计的动态:探索采用 IFRS 对公司财务报告和业务战略的影响
  • 批准号:
    24K16488
  • 财政年份:
    2024
  • 资助金额:
    $ 54.09万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Mighty Accounting - Accountancy Automation for 1-person limited companies.
Mighty Accounting - 1 人有限公司的会计自动化。
  • 批准号:
    10100360
  • 财政年份:
    2024
  • 资助金额:
    $ 54.09万
  • 项目类别:
    Collaborative R&D
Accounting for the Fall of Silver? Western exchange banking practice, 1870-1910
白银下跌的原因是什么?
  • 批准号:
    24K04974
  • 财政年份:
    2024
  • 资助金额:
    $ 54.09万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
A New Direction in Accounting Education for IT Human Resources
IT人力资源会计教育的新方向
  • 批准号:
    23K01686
  • 财政年份:
    2023
  • 资助金额:
    $ 54.09万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
An empirical and theoretical study of the double-accounting system in 19th-century American and British public utility companies
19世纪美国和英国公用事业公司双重会计制度的实证和理论研究
  • 批准号:
    23K01692
  • 财政年份:
    2023
  • 资助金额:
    $ 54.09万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
An Empirical Analysis of the Value Effect: An Accounting Viewpoint
价值效应的实证分析:会计观点
  • 批准号:
    23K01695
  • 财政年份:
    2023
  • 资助金额:
    $ 54.09万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Accounting model for improving performance on the health and productivity management
提高健康和生产力管理绩效的会计模型
  • 批准号:
    23K01713
  • 财政年份:
    2023
  • 资助金额:
    $ 54.09万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
CPS: Medium: Making Every Drop Count: Accounting for Spatiotemporal Variability of Water Needs for Proactive Scheduling of Variable Rate Irrigation Systems
CPS:中:让每一滴水都发挥作用:考虑用水需求的时空变化,主动调度可变速率灌溉系统
  • 批准号:
    2312319
  • 财政年份:
    2023
  • 资助金额:
    $ 54.09万
  • 项目类别:
    Standard Grant
New Role of Not-for-Profit Entities and Their Accounting Standards to Be Unified
非营利实体的新角色及其会计准则将统一
  • 批准号:
    23K01715
  • 财政年份:
    2023
  • 资助金额:
    $ 54.09万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Improving Age- and Cause-Specific Under-Five Mortality Rates (ACSU5MR) by Systematically Accounting Measurement Errors to Inform Child Survival Decision Making in Low Income Countries
通过系统地核算测量误差来改善特定年龄和特定原因的五岁以下死亡率 (ACSU5MR),为低收入国家的儿童生存决策提供信息
  • 批准号:
    10585388
  • 财政年份:
    2023
  • 资助金额:
    $ 54.09万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了