Using a chemical biology approach to develop novel inhibitors of mitochondrial oxidative phosphorylation for the treatment of ovarian cancer

使用化学生物学方法开发用于治疗卵巢癌的新型线粒体氧化磷酸化抑制剂

• 批准号: 10513296
• 负责人: Manish S Patankar
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10513296
• 关键词: Active Learning; Address; Age; Age Years; Apoptosis; Benzoquinones; Biochemical; Biological; Biological Assay; Biological Response Modifier Therapy; Biology; Biometry; Cancer Biology; Cancer Model; Cancer cell line; Cell Death; Cell Death Inhibition; Cells; Characteristics; Chemicals; Clinical Management; Clinical Trials; Curcumin; DNA Damage; DNA Repair; DNA strand break; Data; Development; Diagnosis; Disease; Dose; Drug Targeting; Electron Transport; Exhibits; FADH2; Female; Female Genital Neoplasms; Future; Genetic Complementation Test; Goals; Healthcare Systems; Incidence; Induction of Apoptosis; Lead; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Metabolic; Metabolic Pathway; Methods; Mitochondria; Modeling; Modernization; Molecular; NADH; Non-Malignant; Ovarian; Ovarian Serous Tumor; Oxidative Phosphorylation; Oxidative Stress; Oxygen; Patients; Periodicity; Pharmaceutical Preparations; Poly(ADP-ribose) Polymerase Inhibitor; Population; Postmenopause; Predisposition; Property; PubChem; Reactive Oxygen Species; Records; Recurrent tumor; Reporting; Research; Screening procedure; Serous; Site; Standardization; TP53 gene; Testing; Therapeutic; Tissues; Toxic effect; Treatment Protocols; Ubiquinone; Veterans; Woman; Work; aerobic glycolysis; age group; aging population; atovaquone; cancer cell; cancer stem cell; cancer therapy; candidate identification; carbonyl compound; cheminformatics; chemotherapeutic agent; chemotherapy; citral; cohort; cost effective; data mining; drug candidate; effective therapy; experimental study; functional group; high standard; high throughput screening; in vivo; inhibitor; innovation; interest; machine learning model; metabolic rate; military veteran; mimetics; model building; mouse model; neoplastic cell; novel; novel anticancer drug; novel strategies; ovarian neoplasm; oxidative damage; pharmacokinetic characteristic; pharmacologic; plumbagin; pre-clinical; preclinical study; protein complex; public repository; scaffold; screening; small molecule; small molecule inhibitor; synergism; targeted agent; tumor; tumor growth; tumor metabolism; tumor microenvironment

The number of women Veterans is rapidly increasing and expected to reach to 16-17% of the total Veteran population within the next two decades. Furthermore, female Veterans are an aging population, the 45-64 age group being the largest cohort. As female Veterans age, an increasing number are expected to present with cancers. Gynecologic tumors constitute 12% of all cancers in women Veterans with ovarian malignancy being the second most common in this group. Ovarian cancer predominantly develops in postmenopausal women. Therefore, the incidence of this cancer is expected to increase as the population ages. Ovarian cancer is an especially lethal cancer with none of the modern treatment regimens showing major benefits on overall survival of patients. Our proposed research focuses on the development of novel oxidative phosphorylation (OXPHOS) inhibitors for the treatment of ovarian cancer. Leads for therapeutics emerging from this work have great potential benefit to women Veterans and is highly significant to the VA Healthcare system. Recurrent tumors, cancer stem cells, and non-malignant cells from the tumor microenvironment engage OXPHOS for their metabolic needs. Therefore, there is renewed interest in developing OXPHOS inhibitors as novel agents for the treatment of cancer. We have identified a group of compounds that inhibit OXPHOS by interfering with ubiquinone in transporting electrons from NADH and FADH2 to molecular oxygen. The compounds we are testing, citral, plumbagin, curcumin, atovaquone and others, have an unsaturated carbonyl functional group that mimics ubiquinone’s benzoquinone substructure. As a result, these compounds interfere in OXPHOS, cause rapid increase in intracellular oxygen radicals that damage DNA, and induce apoptosis through the activation of p53. Such ubiquinone mimetics are therefore candidates for cancer therapy. However, the OXHPOS inhibitors we have examined so far, show poor potency and pharmacokinetic characteristics. In this application we propose to employ rapid and cost-effective computational approaches to identify novel and potent OXPHOS inhibitors with the goal of developing leads for treatment of high-grade serous ovarian tumors. In Aim 1, we will develop and validate a data mining pipeline to identify potent and drug-like OXPHOS inhibitors from extensive assay data available in PubChem public repository. In Aim 2 we will employ a machine learning model, based on previous screening data, to guide selection of new compounds for iterative screening in cell biological assays reporting on different aspects of the OXPHOS pathway. In Aim 3, we will test combination dosing of OXPHOS and PARP inhibitors for synergistic potency and efficacy in ovarian cancer models. The methods developed here could be applied generally in leveraging prior assay data to build models that guide iterative screening as a more efficient approach than standard high throughput screening. The proposed studies should help us to identify the most promising biochemical targets and inhibitory compound classes for OXPHOS-targeted ovarian cancer therapies. Lead OXPHOS inhibitors discovered through our approach will be tested in future clinical trials that include women Veterans diagnosed for high grade serous ovarian cancer.

退伍军人的数量迅速增加，预计将达到退伍军人总数的16-17％ 在接下来的二十年中的人口。此外，女退伍军人是老龄化的人口，年龄为45-64岁 小组是最大的队列。随着女性退伍军人的年龄，预计会有越来越多的人 癌症。妇科肿瘤占卵巢恶性肿瘤的所有癌症的12％ 该组中第二大的最常见。绝经后妇女主要发展卵巢癌。 因此，随着人口年龄的增长，该癌症的事件预计将增加。卵巢癌是 特别是致命的癌症，没有任何现代治疗方案显示出对整体生存的主要好处 患者。我们提出的研究重点是新型氧化磷酸化（OXPHOS）的发展 治疗卵巢癌的抑制剂。从这项工作中出现的治疗的铅具有很大的潜力 对女性退伍军人的好处，对VA医疗保健系统非常重要。复发性肿瘤，癌症 细胞和来自肿瘤微环境的非恶性细胞可满足其代谢需求。 因此，人们对开发OXPHOS抑制剂作为治疗的新型药物有新的兴趣 癌症。我们已经确定了一组通过干扰泛氨酮在 将电子从NADH和FADH2运输到分子氧。我们正在测试的化合物，柠檬酸， Plumbagin，Curcumin，Atovaquone等人有一个不饱和的羰基功能组，可以模仿 泛酮的苯喹酮子结构。结果，这些化合物在OXPHOS中的干扰会导致快速 增加细胞内氧自由基，损害DNA，并通过p53的激活诱导凋亡。 因此，这种泛氨基酮模拟物是癌症治疗的候选者。但是，OXHPOS抑制剂我们 到目前为止已经检查了效力和药代动力学特征不佳。在此申请中，我们提出 采用快速且具有成本效益的计算方法来识别新颖和潜在的OXPHOS抑制剂 目的是开发用于治疗高级浆液卵巢肿瘤的铅。在AIM 1中，我们将发展 并验证数据挖掘管道，以从广泛的测定数据中识别潜在和类似药物的OXPHOS抑制剂 可在PubChem公共存储库中找到。在AIM 2中，我们将基于以前的机器学习模型 筛选数据，以指导新化合物的选择，用于细胞生物学测定中的迭代筛查 在Oxphos途径的不同方面。在AIM 3中，我们将测试OXPHOS和PARP的组合剂量 卵巢癌模型中协同效力和效率的抑制剂。这里开发的方法可能是 通常应用于利用先前的测定数据来构建模型，以指导迭代筛选为更有效的效率 方法比标准高通量筛选。拟议的研究应该帮助我们确定最多 有望的生化靶标和抑制性化合物的卵巢癌疗法。 通过我们的方法发现的铅Oxphos抑制剂将在以后的临床试验中进行测试，其中包括 诊断为高级浆液卵巢癌的女退伍军人。