Biological and Pharmacological Evaluations of RhoGEF, GGTase I and Rho kinase inh

RhoGEF、GGTase I 和 Rho 激酶 inh 的生物学和药理学评价

基本信息

  • 批准号:
    7882868
  • 负责人:
  • 金额:
    $ 19.8万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-05-01 至 2010-04-30
  • 项目状态:
    已结题

项目摘要

Program 3 long-term goal is to discover novel anti cancer drugs based on inhibiting the function of persistently activated Rho GTPases in cancer. Rho GTPases are frequently found aberrantly activated in human cancers. For example, RhoC overexpression is common in many cancers such as breast cancer and is associated with metastasis and poor prognosis. Furthermore, many guanine nucleotide exchange factors (GEFs) which activate Rho induce malignant transformation and some such as Tiaml (RaclGEF) and LARG (RhoA and RhoC GEF) have been implicated in human cancer. Rho proteins such as RhoA, RhoC and Rac 1 require prenylation by geranylgeranyltransferase I (GGTase I) for their ability to induce uncontrolled growth, invasion and transformation. Finally, RhoA and RhoC require Rho kinase (ROCK) for their transforming activity. The hypothesis upon which this program of the NCDDG is based is that inhibitors of GGTase I, RhoGEFs and ROCK will reverse malignant transformation of human cancers with aberrant Rho function. Program 3 will interact very closely with Programs 1 and 2 as well as Cores A and B to test this hypothesis. To this end, the specific aims of Program 3 are: Specific Aim 1; To determine the potency and selectivity in vitro and in cultured cells of GGTase I, RhoGEF and ROCK inhibitors from Program 1 and Core B. We will determine whether GGTase I inhibitors are selective for GGTase I over farnesyltransferase; whether RhoGEF inhibitors are selective for Tiaml or LARG over ITSN, Dbs and m-SOS-1 and whether ROCK inhibitors are selective for ROCK I or ROCK II over other ser/thr kinases as well as tyr kinase. Specific Aim 2; To determine the effects of GGTase I, RhoGEF and ROCK inhibitors on signaling, proliferation, cell cycle progression and apoptosis. We will determine whether cancer cells where Rho function is aberrantly activated are more sensitive to inhibitors of GGTase I, RhoGEF and ROCK (i.e. whether cancer cells that overexpress RhoC or activated Tiaml or LARG are more sensitive to inhibition of proliferation and induction of apoptosis by these inhibitors). We will also determine if aberrant activation of Rho function by overexpression of RhoC or activated Tiaml or LARG result in activation of PI3K/Akt pathway, induction of survivin expression and/or suppression of the expression of Bax, p21waf and p27kip; and whether the inhibitors antagonize this. Specific Aim 3: To determine the anti tumor efficacy, pharmacodynamics, pharmacokinetics and toxicity of GGTase I, RhoGEF and ROCK inhibitors. We will use murine and human cells that overexpress RhoA, RhoC, Racl, activated Tiaml and LARG as well as other genes that activate Rho such as EGFR and Ras to determine if tumor cells with aberrantly activated Rho GTPases are more sensitive to inhibition of tumor growth in animal models. We will also determine if inhibition of tumor growth in animal models correlates with inhibition of Rho function in tumors and whether the selected inhibitors have favorable pharmacokinetic and pharmacodynamic properties and lack toxicity. The proposed studies, coupled with those of Programs 1 and 3 and Core B will lead to the identification of potent and selective inhibitors of GGTase I, RhoGEF and ROCK that will thwart the aberrant activation of Rho protein and inhibit malignant transformation of cancer cells.
计划3的长期目标是发现基于抑制持续激活的功能的新型抗癌药物 肿瘤中的Rho GTP酶。Rho GTP酶在人类癌症中经常被发现异常激活。例如,RHOC 过度表达在许多癌症中很常见,如乳腺癌,并与转移和预后不良有关。 此外,许多激活Rho的鸟嘌呤核苷酸交换因子(Gef)可诱导恶性转化。 一些药物,如TIAML(Raclgef)和LARG(RhoA和Rhoc egf)与人类癌症有关联。Rho RhoA、RhoC和Rac-1等蛋白质需要香叶基香叶基转移酶I(GGTase I)的预烯基化才能发挥作用 诱导不受控制的生长、入侵和转化。最后,RhoA和Rhoc需要Rho Kinase(ROCK)来实现 它们的转化活动。NCDDG的这一计划所基于的假设是 GGTase I、RhoGEF和ROCK将逆转Rho异常的人类癌症的恶变 功能。程序3将与程序1和2以及核心A和B进行非常密切的交互,以检验这一假设。 为此,方案3的具体目标是: 特异性目的1;测定GGTase I在体外和培养细胞中的效力和选择性, 我们将确定GGTase I抑制剂 对GGTase I的选择性高于对法尼基转移酶的选择性;Rhogef抑制剂对Tiaml或 在ITSN、DBS和m-SOS-1上的LARG以及ROCK抑制剂对ROCK I或ROCK II的选择性 胜过其他丝氨酸/苏氨酸激酶和酪氨酸激酶。具体目标2:确定GGTase I的作用, Rhogef和ROCK抑制剂对信号、增殖、细胞周期进展和细胞凋亡的影响。我们会 确定Rho功能异常激活的癌细胞是否对抑制剂更敏感 GGTase I、Rhogef和ROCK(即,过表达RhoC或激活的Tiaml或 LARG对这些抑制物抑制增殖和诱导细胞凋亡更为敏感)。我们 还将确定Rho功能是否通过RhoC或激活的Tiaml或LARG的过度表达而异常激活 结果激活PI3K/Akt通路,诱导Survivin表达和/或抑制Bax的表达, P21waf和p27kip;以及抑制剂是否拮抗这一点。特定目标3:确定抗肿瘤药物 GGTase I、Rhogef和ROCK抑制剂的疗效、药效学、药代动力学和毒性。 我们将使用过表达RhoA、RhoC、Racl、激活的Tiaml和LARG的小鼠和人类细胞作为 以及其他激活Rho的基因,如EGFR和RAS,以确定肿瘤细胞是否异常 在动物模型中,激活的Rho GTP酶对抑制肿瘤生长更敏感。我们还将 确定在动物模型中抑制肿瘤生长是否与肿瘤中Rho功能抑制相关 以及所选抑制剂是否具有良好的药代动力学和药效学特性以及 缺乏毒性。拟议的研究,加上方案1和方案3以及核心B的研究,将导致 GGTase I、Rhogef和ROCK的有效和选择性抑制剂的鉴定 激活Rho蛋白,抑制癌细胞恶性转化。

项目成果

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SAID M SEBTI其他文献

SAID M SEBTI的其他文献

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{{ truncateString('SAID M SEBTI', 18)}}的其他基金

Targeting Mutant KRAS for Cancer Therapy
针对突变 KRAS 进行癌症治疗
  • 批准号:
    9437725
  • 财政年份:
    2016
  • 资助金额:
    $ 19.8万
  • 项目类别:
Targeting Mutant KRAS for Cancer Therapy
针对突变 KRAS 进行癌症治疗
  • 批准号:
    10004247
  • 财政年份:
    2016
  • 资助金额:
    $ 19.8万
  • 项目类别:
Targeting Mutant KRAS for Cancer Therapy
针对突变 KRAS 进行癌症治疗
  • 批准号:
    9233953
  • 财政年份:
    2016
  • 资助金额:
    $ 19.8万
  • 项目类别:
Targeting Mutant KRAS for Cancer Therapy
针对突变 KRAS 进行癌症治疗
  • 批准号:
    10204898
  • 财政年份:
    2016
  • 资助金额:
    $ 19.8万
  • 项目类别:
Targeting Mutant KRAS for Cancer Therapy
针对突变 KRAS 进行癌症治疗
  • 批准号:
    10413104
  • 财政年份:
    2016
  • 资助金额:
    $ 19.8万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    7882871
  • 财政年份:
    2009
  • 资助金额:
    $ 19.8万
  • 项目类别:
Targeting Signal Transduction Pathways for Cancer Drug Discovery
针对癌症药物发现的信号转导途径
  • 批准号:
    8034268
  • 财政年份:
    2007
  • 资助金额:
    $ 19.8万
  • 项目类别:
Targeting Signal Transduction Pathways for Cancer Drug Discovery
针对癌症药物发现的信号转导途径
  • 批准号:
    7759306
  • 财政年份:
    2007
  • 资助金额:
    $ 19.8万
  • 项目类别:
Targeting Signal Transduction Pathways for Cancer Drug Discovery
针对癌症药物发现的信号转导途径
  • 批准号:
    7767743
  • 财政年份:
    2007
  • 资助金额:
    $ 19.8万
  • 项目类别:
Targeting Signal Transduction Pathways for Cancer Drug Discovery
针对癌症药物发现的信号转导途径
  • 批准号:
    7581046
  • 财政年份:
    2007
  • 资助金额:
    $ 19.8万
  • 项目类别:

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口服抗肿瘤药物的获取延迟
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  • 批准号:
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    2007
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