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Gold-derived Therapeutic Compounds for Disease Application

用于疾病应用的金衍生治疗化合物

基本信息

批准号：
10598722
负责人：
Samuel Gorman Awuah
金额：
$ 7.03万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-04 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10598722
关键词：
Adopted Aging Antineoplastic Agents Apoptosis Autophagocytosis Biogenesis Bioinformatics Biometry Breast Cancer Cell Cancer Biology Cancer Model Cardiovascular system Cell physiology Cellular Metabolic Process Cessation of life Chemicals Complex Comprehension Data Dependence Development Disease Disease Progression Drug Kinetics Electron Transport Environment Event FRAP1 gene Fostering Foundations Gene Expression Goals Gold Gold Compounds Growth Immune response Impairment In Vitro Knowledge Lead Ligands Malignant Neoplasms Maximum Tolerated Dose Medical Metabolic Metals Metformin Mitochondria Modality Modeling Modification Molecular Morphology Neoplasm Metastasis Nerve Degeneration Normal Cell Oxidative Phosphorylation Pathway interactions Patients Pharmacodynamics Physiological Processes Process Prognostic Marker Proteins Proteomics Reagent Research Respiration Respiratory Chain Role Rotenone Signal Transduction Structure Structure-Activity Relationship Synthesis Chemistry Testing Therapeutic Therapeutic Index Time Toxic effect Translating Work analog anti-cancer antitumor agent antitumor effect base cancer cell cell growth clinical efficacy driving force drug development drug discovery improved in vitro Assay in vivo innovation insight mitochondrial dysfunction mitochondrial metabolism mouse model novel novel strategies novel therapeutic intervention novel therapeutics patient derived xenograft model programs rational design response scaffold skills small molecule targeted agent therapeutic target tool translational therapeutics triple-negative invasive breast carcinoma tumor tumor growth tumor metabolism tumor progression tumor xenograft uptake

项目摘要

Mitochondrial metabolism is crucial for physiological processes spanning cell signaling & growth, gene expression, and immune response. At the same time, mitochondrial dysfunction contributes to neurodegenerative, cardiovascular, ageing, and cancer progression. Current strategies with metal agents or organic small-molecule probes that target mitochondria have either poor target potency (e.g metformin), unclear mechanisms, or their toxicity (e.g rotenone) precludes in vivo application. Thus, potent, selective, and in vivo tolerable chemical reagents are urgently needed. The major objective of our research program is to develop novel gold-based compounds as agents that selectively alter and probe distinct mitochondrial functions. The significance of this proposal is the development of new chemical modulators for the often- intractable mitochondrial pathways including OXPHOS. Our research program has made significant contributions already by developing biologically active gold compounds that either inhibit OXPHOS (AuDTC), increase OXPHOS and mitochondrial biogenesis, or modify mitochondrial structure in vitro and in vivo. We have made foundational discoveries regarding mitochondrial metabolism in triple negative breast cancer (TNBC), defined how complex I impact cellular processes, developed cutting-edge tools to determine the underlying cellular mechanisms, and established therapeutic platforms to inhibit mitochondrial complex I. We hypothesize that mitochondrial metabolism are a driving force for disease progression in TNBC. Defining the mechanisms of mitochondrial metabolism in TNBC provides insights into the dependence of aggressive tumors on mitochondria for growth. This supplement will allow Mr. Omar Bojang to further hone his skills in translational therapeutics. His results will assist in determining the role of mitochondrial complex I inhibition in TNBC. He will look at modifications of lead AuDTC compound in perturbing the mitochondrial mechanisms at the molecular level and establish novel therapeutic modalities at the organismal level.

线粒体代谢对于细胞信号传导和生长、基因等生理过程至关重要表达和免疫反应。同时，线粒体功能障碍也会导致神经退行性疾病、心血管、衰老和癌症进展。当前使用金属剂的策略或靶向线粒体的有机小分子探针的靶向效力较差（例如二甲双胍），不清楚机制或其毒性（例如鱼藤酮）妨碍了体内应用。因此，有效的、选择性的、体内迫切需要可耐受的化学试剂。我们研究计划的主要目标是开发新型金基化合物作为选择性改变和探测不同线粒体的试剂功能。该提案的意义在于开发新的化学调节剂，用于经常棘手的线粒体途径，包括 OXPHOS。我们的研究计划取得了重大成果通过开发具有生物活性的金化合物，可以抑制 OXPHOS (AuDTC)，增加 OXPHOS 和线粒体生物发生，或在体外和体内改变线粒体结构。我们有在三阴性乳腺癌（TNBC）线粒体代谢方面取得了基础性发现，定义了 I 对细胞过程的影响程度，开发了尖端工具来确定潜在的细胞机制，并建立了抑制线粒体复合物 I 的治疗平台。我们假设线粒体代谢是 TNBC 疾病进展的驱动力。定义 TNBC 线粒体代谢机制提供了对侵袭性肿瘤依赖性的见解线粒体上的生长。该补充材料将使 Omar Bojang 先生进一步磨练他的翻译技能疗法。他的结果将有助于确定线粒体复合物 I 抑制在 TNBC 中的作用。他会从分子水平上观察先导 AuDTC 化合物的修饰对线粒体机制的干扰水平并在有机体水平上建立新的治疗方式。