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.

女性退伍军人人数正在迅速增加，预计将达到退伍军人总数的 16-17% 此外，女性退伍军人人口正在老龄化，年龄在 45-64 岁之间。 随着女性退伍军人年龄的增长，预计会有越来越多的人出现这种情况。 妇科肿瘤占女性退伍军人所有癌症的 12%。 卵巢癌是该组中第二常见的癌症，主要发生于绝经后妇女。 因此，随着人口老龄化，这种癌症的发病率预计会增加。 尤其是致命的癌症，没有一种现代治疗方案对总体生存率显示出重大益处 我们提出的研究重点是新型氧化磷酸化（OXPHOS）的开发。 这项工作中出现的治疗卵巢癌的抑制剂具有巨大的潜力。 对女性退伍军人有益，对退伍军人管理局医疗保健系统非常重要。 肿瘤微环境中的细胞和非恶性细胞利用 OXPHOS 来满足其代谢需求。 因此，人们对开发 OXPHOS 抑制剂作为治疗 我们已经鉴定出一组通过干扰泛醌来抑制 OXPHOS 的化合物。 将电子从 NADH 和 FADH2 传输到分子氧，我们正在测试的化合物是柠檬醛， 白花丹素、姜黄素、阿托伐醌等具有不饱和羰基官能团，可模仿 因此，这些化合物会干扰 OXPHOS，导致快速发生。 细胞内氧自由基的增加会损伤 DNA，并通过激活 p53 诱导细胞凋亡。 因此，此类泛醌模拟物是癌症治疗的候选药物。然而，我们使用 OXHPOS 抑制剂。 迄今为止，我们发现该药物的效力和药代动力学特征较差。 采用快速且经济高效的计算方法来识别新型且有效的 OXPHOS 抑制剂 在目标 1 中，我们将开发治疗高级别浆液性卵巢肿瘤的线索。 并验证数据挖掘管道，以从大量分析数据中识别有效的药物样 OXPHOS 抑制剂 在 PubChem 公共存储库中，我们将采用基于之前的机器学习模型。 筛选数据，指导选择新化合物以在细胞生物测定报告中进行迭代筛选 在目标 3 中，我们将测试 OXPHOS 和 PARP 的联合给药。 这里开发的方法可能是在卵巢癌模型中具有协同效力和功效的抑制剂。 通常应用于利用先前的分析数据来构建模型，指导迭代筛选作为更有效的方法 所提出的研究应该帮助我们确定最重要的方法。 OXPHOS 靶向卵巢癌治疗的生化靶点和抑制性有希望的化合物类别。 通过我们的方法发现的先导 OXPHOS 抑制剂将在未来的临床试验中进行测试，包括 被诊断患有高级别浆液性卵巢癌的女性退伍军人。