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：
8238575
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 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8238575
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 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. PUBLIC HEALTH RELEVANCE: This application describes the discovery of a novel cancer therapeutic agent, ON1231320, which could find a wide application in the treatment of some of the most difficult-to-treat cancers that are traditionally resistant to chemotherapy. In this application, we propose to develop preclinical pharmacology, and efficacy profiles for the ON1231320 in preparation to a Phase 1 study in cancer patients. Because this compound is highly effective in various combinations with conventional chemotherapy, the lack of bone marrow toxicity may be beneficial for testing novel combinations for advanced cancers, including tumors resistant to conventional chemotherapy.

描述（由申请人提供）：伊马替尼最近成功治疗费城染色体阳性慢性粒细胞白血病，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类激酶组可以被合理选择性和有效的抑制剂所靶向，因此迫切需要制定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 ATP 竞争性激酶抑制剂化合物库。使用我们收集的新型化合物（大约 2,000 种），我们测试了一组 16 个培养的肿瘤细胞系，以确定这些化合物诱导细胞凋亡的能力。这次搜索发现了一种化合物 ON1231320，它对整个 16 种肿瘤细胞系具有显着的细胞毒性，而对正常细胞几乎没有或没有细胞毒性。针对一组 285 种激酶的激酶抑制测定表明，该化合物对 Plk2/Snk（一种参与中心体复制和有丝分裂进展的激酶）具有显着的特异性。最重要的是，Plk2 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（称为瓦伯格效应），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。最近的一项研究表明，在HCT116人结肠癌细胞系中靶向消除SCO2基因会导致线粒体呼吸功能的消除，并且PLK2是SCO2-/-细胞中表达量最高的基因。即使线粒体呼吸缺陷的人类癌细胞中 PLK2 水平适度降低，也会导致其在小鼠体内形成异种移植物的能力消失。我们的结果表明 ON1231320 是一种有效的肿瘤细胞死亡诱导剂，并且具有出色的体内安全性。我们建议在体外和体内研究这种化合物对肿瘤生长的影响，以确定 ON1231320 如何作为一种新型癌症化疗药物。该提案的目的是： 1. 确定ON01231320抑制Plk2的动力学； 2. 确定ON1231320对Plk2介导的下游信号事件的影响，并评估其在缺氧、基因毒性和呼吸缺陷环境下对肿瘤细胞生长的影响； 3. 表征 ON1231320 在异种移植模型中的 PK 特性，以确定抑制肿瘤生长所需的 Plk2 抑制程度，评估 ON1231320 浓度与化合物抗肿瘤活性的关系，并评估使用 PBMN 作为替代物的有效性; 4. 进一步探讨ON1231320与奥沙利铂、5-氟尿嘧啶、紫杉醇、阿霉素等细胞毒性抗癌药物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效果。公共健康相关性：本申请描述了一种新型癌症治疗剂 ON1231320 的发现，该药物可广泛应用于治疗一些传统上对化疗耐药的最难治疗的癌症。在此应用中，我们建议开发 ON1231320 的临床前药理学和功效概况，为癌症患者的 1 期研究做准备。由于该化合物在与常规化疗的各种组合中都非常有效，因此缺乏骨髓毒性可能有利于测试晚期癌症的新组合，包括对常规化疗耐药的肿瘤。