Targeting Mitotic Kinases Inhibitors for Cancer Therapy

靶向有丝分裂激酶抑制剂用于癌症治疗

基本信息

项目摘要

DESCRIPTION (provided by applicant): The recent success of imatinib for the treatment of Philadelphia chromosome positive chronic myelogenous leukemia has made tyrosine and serine/threonine kinases major targets for cancer therapy. As only a small fraction of the human kinome can currently be targeted by a reasonably selective and potent inhibitor, there is an urgent need to develop strategies for efficient discovery and optimization of new inhibitors. Towards this goal, we have recently developed a compound library of ATP-competitive kinase inhibitors. Using our collection of novel compounds (approximately 2,000), we tested a panel of 16 cultured tumor cell lines for the ability of these compounds to induce apoptotic death. This search revealed a compound, ON1231320, that had remarkable cytotoxicity against the entire panel of 16 tumor cell lines, with little or no cytotoxicity towards normal cells. Kinase inhibition assays against a panel of 285 kinases revealed that this compound had a remarkable specificity towards Plk2/Snk, a kinase involved in centrosome duplication and mitotic progression. Most importantly, Plk2 has recently been implicated as one of the kinases that links cellular metabolism to cell cycle. Mitochondrial dysfunction with increased dependence on glycolysis is frequently observed in cancer cells (known as the Warburg effect) and identification of pathways that promote cell survival under conditions of mitochondrial dysfunction have therapeutic implications. In a recent study, it has been shown that targeted ablation of SCO2 gene in HCT116 human colon cancer cell line results in the ablation of mitochondrial respiration and that PLK2 is the most highly expressed gene in SCO2-/-cells. Even a modest reduction in PLK2 levels in human cancer cells with defects in mitochondrial respiration results in the elimination of their ability to form xenografts in mice. Our results show that ON1231320 is a potent inducer of tumor cell death and has an excellent safety profile in vivo. We propose to study the effects of this compound on tumor growth in vitro and in vivo to determine how ON1231320 will serve as a novel cancer chemotherapeutic. The aims of the proposal are: 1. To determine the kinetics of inhibition of Plk2 by ON01231320; 2. To determine the effects of ON1231320 on downstream signaling events mediated by Plk2 and evaluate its effect on tumor cell growth under hypoxic, genotoxic and defective respiratory contexts; 3. Characterize the PK properties of ON1231320 in xenograft models to determine the degree of inhibition of Plk2 that is required for inhibition of tumor growth and assess how ON1231320 concentrations are related to antitumor activity of the compound and to evaluate the validity of using PBMN as surrogates; and 4. To further explore the effects of combination therapy using ON1231320 and cytotoxic anti-cancer agents such as oxaliplatin, 5-fluorouracil, paclitaxel and doxorubicin to induce apoptosis and tumor regression in breast and colorectal cancer model systems.
描述(由申请人提供):最近伊马替尼成功治疗费城染色体阳性慢性髓性白血病,使酪氨酸和丝氨酸/苏氨酸激酶成为癌症治疗的主要靶点。由于目前只有一小部分人激酶组可以被合理选择性和有效的抑制剂靶向,因此迫切需要开发有效发现和优化新抑制剂的策略。为了实现这一目标,我们最近开发了一个化合物库的ATP竞争性激酶抑制剂。使用我们收集的新化合物(约2,000种),我们测试了一组16种培养的肿瘤细胞系,以了解这些化合物诱导细胞凋亡的能力。该研究揭示了一种化合物ON 1231320,其对整个16种肿瘤细胞系具有显著的细胞毒性,对正常细胞具有很少或没有细胞毒性。对一组285种激酶的激酶抑制试验表明,该化合物对Plk 2/Snk(一种参与中心体复制和有丝分裂进程的激酶)具有显著的特异性。最重要的是,Plk 2最近被认为是将细胞代谢与细胞周期联系起来的激酶之一。在癌细胞中经常观察到对糖酵解依赖性增加的线粒体功能障碍(称为瓦尔堡效应),并且鉴定在线粒体功能障碍条件下促进细胞存活的途径具有治疗意义。在最近的一项研究中,已经表明,靶向消融HCT 116人结肠癌细胞系中的SCO 2基因导致线粒体呼吸的消融,并且PLK 2是SCO 2-/-细胞中表达最高的基因。即使是线粒体呼吸缺陷的人癌细胞中PLK 2水平的适度降低也会导致其在小鼠中形成异种移植物的能力的消除。我们的研究结果表明,ON 1231320是一种有效的肿瘤细胞死亡诱导剂,并具有良好的体内安全性。我们建议研究这种化合物在体外和体内对肿瘤生长的影响,以确定ON 1231320将如何作为一种新的癌症化疗药物。该提案的目的是:1。确定ON 01231320抑制Plk 2的动力学; 2.确定ON 1231320对Plk 2介导的下游信号传导事件的影响,并评估其在缺氧、遗传毒性和呼吸缺陷环境下对肿瘤细胞生长的影响; 3.表征ON 1231320在异种移植模型中的PK性质,以确定抑制肿瘤生长所需的Plk 2抑制程度,并评估ON 1231320浓度如何与化合物的抗肿瘤活性相关,并评估使用PBMN作为替代物的有效性;和4.进一步探索使用ON 1231320和细胞毒性抗癌剂(如奥沙利铂、5-氟尿嘧啶、紫杉醇和多柔比星)的联合治疗在乳腺癌和结直肠癌模型系统中诱导细胞凋亡和肿瘤消退的作用。

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:
    $ 35.17万
  • 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:
    $ 35.17万
  • 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:
    $ 35.17万
  • 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:
    $ 35.17万
  • 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:
    $ 35.17万
  • 项目类别:
Targeting CDK4 in TGS-B Inactivated Gastrointestinal Cancers
TGS-B 灭活胃肠道癌中靶向 CDK4
  • 批准号:
    8744873
  • 财政年份:
    2013
  • 资助金额:
    $ 35.17万
  • 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:
    $ 35.17万
  • 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:
    $ 35.17万
  • 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:
    $ 35.17万
  • 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:
    $ 35.17万
  • 项目类别:

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