Targeting CDK4 in TGS-B Inactivated Gastrointestinal Cancers

TGS-B 灭活胃肠道癌中靶向 CDK4

基本信息

  • 批准号:
    8744873
  • 负责人:
  • 金额:
    $ 17.08万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-09-01 至 2016-08-31
  • 项目状态:
    已结题

项目摘要

Recent studies have shown that TGF-B inhibits cell proliferation by blocking cell cycle progression at the G1 phase of the cell cycle and hence, is thought to function as a tumor suppressor protein. Most human cancers appear to have lost their growth-inhibitory response to TGF-B. Our preliminary studies show that foregut cancers with inactivation of TGF-B signaling express high levels of cyclin D1 and CDK4 levels, suggesting that the deregulated expression of these proteins may contribute to the development of these tumors. Flavopiridol, an established Cdk inhibitor used in treatment protocols for certain cancers, is known to inhibit most known CDKs especially against CDKs 7, 8 and 9, is thought to be largely responsible for the toxic side effects caused by this drug in clinical trials. In light of these observations, we have screened a compound library of kinase inhibitors for CDK-4 specific inhibition and isolated two novel molecules (ON55290 and ON27900) which exhibit CDK4 inhibitory activity. In this application, we propose to carry out pre-clinical studies to test the usefulness of these molecules in gastrointestinal cancer therapy. The aims of the proposal are: 1. To further validate the role of CDK4 in Elf+/-, Elf+/-:Smad3+/- tumor model system through evaluation of tumor incidence in CDK4+/V El+/- : CDK4+/-: Elf/Elf[+]-Smad4[+/-] and CDK4[+/-]; Elf¿/Elf+:Smad4+/- mice. 2. (a) To expand the chemical library in an effort to understand the structure-activity relationship (SAR) of CDK4 inhibitors and (b) to conduct a detailed kinetic analysis of CDK4 inhibition by ON55290 and ON27900 to gain critical information on the mechanisms by which these compounds elicit their inhibitory effects on CDK4. 3. To determine the molecular mechanisms by which ON55290 and ON27900 bring about growth arrest and death of human gastrointestinal cancer cells. 4. To assess the safety and pharmacokinetics of the candidate drug in animal models of gastrointestinal cancers that develop in the TGF-f3 inactivated state.
最近的研究表明,TGF-β通过在细胞周期的G1期阻断细胞周期进程来抑制细胞增殖,因此,被认为是一种肿瘤抑制蛋白。大多数人类癌症似乎已经失去了对TGF-B的生长抑制反应。我们的初步研究表明,前肠癌与TGF-β信号的失活表达高水平的细胞周期蛋白D1和CDK 4的水平,这表明这些蛋白质的表达失调可能有助于这些肿瘤的发展。Flavopiridol是一种用于某些癌症治疗方案的Cdk抑制剂,已知可抑制大多数已知的CDK,特别是CDK 7、8和9,被认为是该药物在临床试验中引起的毒副作用的主要原因。根据这些观察结果,我们筛选了一个化合物库的激酶抑制剂的CDK-4特异性抑制和分离的两个新的分子(ON 55290和ON 27900),表现出CDK-4抑制活性。在本申请中,我们建议进行临床前研究,以测试这些分子在胃肠道癌症治疗中的有用性。该提案的目的是: 1.通过评价CDK 4 +/V El+/-:CDK 4 +/-:Elf/Elf[+]-Smad 4 [+/-]和CDK 4 [+/-]; Elf/Elf+:Smad 4 +/-小鼠的肿瘤发生率,进一步验证CDK 4在Elf+/-,Elf+/-:Smad 3 +/-肿瘤模型系统中的作用。 2. (a)为了扩展化学文库以努力理解CDK 4抑制剂的结构-活性关系(SAR),以及(B)通过ON 55290和ON 27900对CDK 4抑制进行详细的动力学分析,以获得关于这些化合物引起其对CDK 4的抑制作用的机制的关键信息。 3.目的:探讨ON55290和ON 27900诱导人胃肠道癌细胞生长停滞和死亡的分子机制。4.评估候选药物在TGF-f3失活状态下发生的胃肠道癌症动物模型中的安全性和药代动力学。

项目成果

期刊论文数量(0)
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E Premkumar Reddy其他文献

IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled
白细胞介素 3 信号传导以及 Src 激酶、JAK 和 STAT 的作用:一个隐蔽的联络被揭示
  • DOI:
    10.1038/sj.onc.1203594
  • 发表时间:
    2000-05-25
  • 期刊:
  • 影响因子:
    7.300
  • 作者:
    E Premkumar Reddy;Anita Korapati;Priya Chaturvedi;Sushil Rane
  • 通讯作者:
    Sushil Rane
Janus kinases: components of multiple signaling pathways
Janus 激酶:多条信号通路的组成部分
  • DOI:
    10.1038/sj.onc.1203925
  • 发表时间:
    2000-11-20
  • 期刊:
  • 影响因子:
    7.300
  • 作者:
    Sushil G Rane;E Premkumar Reddy
  • 通讯作者:
    E Premkumar Reddy
The myb gene family in cell growth, differentiation and apoptosis
细胞生长、分化和凋亡中的 myb 基因家族
  • DOI:
    10.1038/sj.onc.1202839
  • 发表时间:
    1999-05-13
  • 期刊:
  • 影响因子:
    7.300
  • 作者:
    Il-Hoan Oh;E Premkumar Reddy
  • 通讯作者:
    E Premkumar Reddy
JAKs, STATs and Src kinases in hematopoiesis
造血过程中的 JAKs、STATs 和 Src 激酶
  • DOI:
    10.1038/sj.onc.1205398
  • 发表时间:
    2002-05-21
  • 期刊:
  • 影响因子:
    7.300
  • 作者:
    Sushil G Rane;E Premkumar Reddy
  • 通讯作者:
    E Premkumar Reddy
Signaling by dual specificity kinases
双特异性激酶的信号传导
  • DOI:
    10.1038/sj.onc.1202251
  • 发表时间:
    1998-09-22
  • 期刊:
  • 影响因子:
    7.300
  • 作者:
    N Dhanasekaran;E Premkumar Reddy
  • 通讯作者:
    E Premkumar Reddy

E Premkumar Reddy的其他文献

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{{ truncateString('E Premkumar Reddy', 18)}}的其他基金

Targeting FL3 and SRC kinases for AML therapy
靶向 FL3 和 SRC 激酶进行 AML 治疗
  • 批准号:
    10658259
  • 财政年份:
    2023
  • 资助金额:
    $ 17.08万
  • 项目类别:
Targeting cell cycle and metabolic pathways of high risk breast cancers using mouse models of hyperinsulinemia
使用高胰岛素血症小鼠模型靶向高风险乳腺癌的细胞周期和代谢途径
  • 批准号:
    10671005
  • 财政年份:
    2020
  • 资助金额:
    $ 17.08万
  • 项目类别:
Targeting cell cycle and metabolic pathways of high risk breast cancers using mouse models of hyperinsulinemia
使用高胰岛素血症小鼠模型靶向高风险乳腺癌的细胞周期和代谢途径
  • 批准号:
    10199970
  • 财政年份:
    2020
  • 资助金额:
    $ 17.08万
  • 项目类别:
Targeting cell cycle and metabolic pathways of high risk breast cancers using mouse models of hyperinsulinemia
使用高胰岛素血症小鼠模型靶向高风险乳腺癌的细胞周期和代谢途径
  • 批准号:
    10029076
  • 财政年份:
    2020
  • 资助金额:
    $ 17.08万
  • 项目类别:
Targeting cell cycle and metabolic pathways of high risk breast cancers using mouse models of hyperinsulinemia
使用高胰岛素血症小鼠模型靶向高风险乳腺癌的细胞周期和代谢途径
  • 批准号:
    10457279
  • 财政年份:
    2020
  • 资助金额:
    $ 17.08万
  • 项目类别:
Targeting Mitotic Kinases Inhibitors for Cancer Therapy
靶向有丝分裂激酶抑制剂用于癌症治疗
  • 批准号:
    8985660
  • 财政年份:
    2012
  • 资助金额:
    $ 17.08万
  • 项目类别:
Targeting Mitotic Kinases Inhibitors for Cancer Therapy
靶向有丝分裂激酶抑制剂用于癌症治疗
  • 批准号:
    8787991
  • 财政年份:
    2012
  • 资助金额:
    $ 17.08万
  • 项目类别:
Targeting Mitotic Kinases Inhibitors for Cancer Therapy
靶向有丝分裂激酶抑制剂用于癌症治疗
  • 批准号:
    8435360
  • 财政年份:
    2012
  • 资助金额:
    $ 17.08万
  • 项目类别:
Targeting Mitotic Kinases Inhibitors for Cancer Therapy
靶向有丝分裂激酶抑制剂用于癌症治疗
  • 批准号:
    8238575
  • 财政年份:
    2012
  • 资助金额:
    $ 17.08万
  • 项目类别:
Role of C-myb in Hematopoiesis and Cancer
C-myb 在造血和癌症中的作用
  • 批准号:
    7629613
  • 财政年份:
    2007
  • 资助金额:
    $ 17.08万
  • 项目类别:

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