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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

批准号：
8787991
负责人：
E Premkumar Reddy
金额：
$ 35.17万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-29 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8787991
关键词：
Ablation Address Advanced Malignant Neoplasm Affect Antineoplastic Agents Apoptosis Apoptotic Behavior Binding Biological Assay Biological Models Bladder Neoplasm Bone Marrow Cancer Model Cancer Patient Cell Cycle Cell Cycle Regulation Cell Death Cell Line Cell Survival Cells Centrosome Cessation of life Clinical Trials Collection Colorectal Cancer Combined Modality Therapy Cultured Tumor Cells Defect Dependence Development Dose Doxorubicin Drug Kinetics Enzymes Event Fluorouracil Genes Glycolysis Goals Growth HCT116 Cells Hela Cells Human Hypoxia Imatinib In Vitro Kinetics Laboratories Lead Libraries Link Malignant - descriptor Malignant Neoplasms Malignant neoplasm of cervix uteri Malignant neoplasm of urinary bladder Mass Spectrum Analysis Mediating Metabolism Mitochondria Mitotic Modification Mus Nocodazole Non-Small-Cell Lung Carcinoma Normal Cell Nude Mice Paclitaxel Pathway interactions Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacology Phase Phase II Clinical Trials Philadelphia Chromosome Positive Chronic Myelogenous Leukemia Phosphotransferases Poison Preparation Property Protein-Serine-Threonine Kinases Proteomics Protocols documentation Publishing Research Proposals Resistance Respiration Role S Phase Safety Sampling Series Signal Transduction Specificity Stress Structure-Activity Relationship Testing Therapeutic Therapeutic Agents Therapeutic Uses Time Tissues Toxic effect Tumor Cell Line Tyrosine Urine Warburg Effect Xenograft Model Xenograft procedure base cancer cell cancer therapy cell growth chemotherapy colon cancer cell line cytotoxic cytotoxicity design drug development drug discovery human PLK1 protein in vivo inhibitor/antagonist killings kinase inhibitor knock-down malignant breast neoplasm mitochondrial dysfunction neoplastic cell new therapeutic target novel osteosarcoma oxaliplatin phase 1 study pre-clinical preclinical study respiratory small molecule libraries success targeted cancer therapy tumor tumor growth tumor xenograft

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。