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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.

线粒体代谢是至关重要的生理过程跨越细胞信号&生长，基因表达和免疫反应。与此同时，线粒体功能障碍有助于神经退行性疾病、心血管疾病、衰老和癌症进展。目前的战略与金属剂或靶向线粒体的有机小分子探针具有较差的靶向效力（例如二甲双胍），机制，或其毒性（如鱼藤酮）排除了体内应用。因此，有效的，选择性的，和在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作为选择性改变和探测不同线粒体的试剂的新型金基化合物功能协调发展的该建议的意义在于开发新的化学调节剂，用于经常- 包括OXPHOS在内的顽固性线粒体途径。我们的研究项目取得了重大进展通过开发生物活性金化合物已经做出了贡献，这些化合物可以抑制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）的线粒体代谢方面取得了基础性发现，定义了复杂的I如何影响细胞过程，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中的线粒体代谢机制提供了对侵袭性肿瘤依赖性的见解在线粒体上生长。这份补充材料将使Omar Bojang先生能够进一步磨练他的翻译技能，治疗学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。他将研究在分子水平上干扰线粒体机制的AuDTC化合物的修饰并在生物体水平上建立新的治疗模式。