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：
10180196
负责人：
Samuel Gorman Awuah
金额：
$ 31.92万
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/10180196
关键词：
4T1 Adopted Animals Antineoplastic Agents Apoptosis Autophagocytosis Biogenesis Bioinformatics Biological Biology Biometry Breast Cancer Cell Cancer Biology Cancer Model Cessation of life Chemicals Complex Data Development Disease Drug Kinetics Drug Targeting Electron Transport Environment Exhibits FRAP1 gene Fostering Goals Gold Gold Compounds Growth Impairment In Vitro Inbred BALB C Mice Knowledge Lead Libraries Ligands Locales Malignant Neoplasms Maximum Tolerated Dose Medical Metabolic Metastatic Neoplasm to the Liver Mitochondria Modeling Modification Morphology Neoplasm Metastasis Normal Cell Normal tissue morphology Outcome Oxidative Phosphorylation Pathway interactions Patients Pharmacodynamics Process Prognostic Marker Property Proteins Proteomics Regimen Research Respiration Respiratory Chain Specificity Structure Structure-Activity Relationship Synthesis Chemistry Testing Therapeutic Therapeutic Agents Therapeutic Index Toxic effect Work analog anti-cancer anticancer activity antitumor agent antitumor effect base cancer cell cell growth clinical efficacy clinical subtypes comparative design drug development drug discovery effective therapy improved in vitro Assay in vivo innovation insight malignant breast neoplasm mitochondrial dysfunction mouse model nanomolar new therapeutic target novel novel strategies novel therapeutic intervention patient derived xenograft model prevent programs response scaffold small molecule targeted agent targeted treatment therapeutic target tool triple-negative invasive breast carcinoma tumor tumor growth tumor xenograft uptake

项目摘要

PROJECT SUMMARY/ABSTRACT. Gold-derived anticancer compounds are promising therapeutic agents for disease applications, including cancer. Triple negative breast cancer (TNBC) is an aggressive clinical subtype of breast cancer that lacks effective therapy. Approximately, 66% of all breast cancer deaths are TNBC-related, hence pragmatic treatment options are sorely needed. Our research program seeks to harness the unique spatial properties and chemical reactivity of gold-based [Au(I) and Au(III)] complexes as a basis for new targeted therapeutic regimen to eliminate TNBC. We have developed gold compound libraries with different scaffolds and distinct mode of action in TNBC cells including modulating mitochondrial biogenesis and morphology. The compounds display high potency in the nanomolar range with >30-fold selectivity to cancer cells over normal cells. Comparative profiling using the NCI-60 screen confirmed toxicity of a lead compound, AuPhos against a panel of breast cancer including TNBC. Preliminary maximum tolerated dose studies in BALB/c mice suggest that different classes of gold compounds can be well tolerated in animals. Additionally, AuPhos exerts profound antitumor effect and prevents liver metastasis in the metastatic 4T1 TNBC mouse model. Mechanism of action studies suggest that the gold compounds target different mitochondrial processes including mitochondrial biogenesis or morphology. We hypothesize that synthetic modification of the gold scaffold will enable the development of a suite of gold-based drugs that are targeted to different mitochondrial locales and biological targets to eliminate TNBC. We will test the hypothesis in this project via the following aims: Aim 1) optimize chemically and functionally diverse gold anticancer agents; Aim 2) Delineate the mechanism of gold-based modulation of mitochondrial function; and Aim 3) Determine the therapeutic index of optimized gold compounds in TNBC mouse models. The outcomes of this project will 1) provide novel gold-based compounds with specificity for mitochondrial function to eliminate TNBC; 2) delineate the mechanism of TNBC inhibition by the developed gold-based compounds; and 3) establish in vivo efficacy and pharmacodynamics of gold anticancer agents. Critically, the compounds generated will provide impetus for targeted therapies for TNBC, which is an unmet need.

项目摘要/摘要。金衍生的抗癌化合物是有前途的治疗剂疾病应用，包括癌症。三阴性乳腺癌（TNBC）是一种侵袭性临床亚型缺乏有效治疗的乳腺癌。大约 66% 的乳腺癌死亡与 TNBC 相关，因此，迫切需要务实的治疗方案。我们的研究计划旨在利用独特的空间金基 [Au(I) 和 Au(III)] 配合物的性质和化学反应性作为新目标的基础消除 TNBC 的治疗方案。我们开发了具有不同支架的金化合物库 TNBC 细胞中独特的作用模式，包括调节线粒体生物发生和形态。这化合物在纳摩尔范围内表现出高效能，对癌细胞的选择性是正常细胞的 30 倍以上细胞。使用 NCI-60 筛选的比较分析证实了先导化合物 AuPhos 对乳腺癌小组，包括 TNBC。 BALB/c 小鼠的初步最大耐受剂量研究表明不同类别的金化合物在动物中具有良好的耐受性。此外，AuPhos 发挥着深远的作用在转移性 4T1 TNBC 小鼠模型中具有抗肿瘤作用并预防肝转移。作用机制研究表明，金化合物针对不同的线粒体过程，包括线粒体生物发生或形态。我们假设金支架的合成修饰将使开发一套针对不同线粒体部位和生物的金基药物消除 TNBC 的目标。我们将通过以下目标来检验该项目中的假设：目标 1) 优化化学和功能多样化的金抗癌剂；目标 2) 描绘金基机制线粒体功能的调节；目标 3) 确定优化金化合物的治疗指数在 TNBC 小鼠模型中。该项目的成果将 1) 提供具有特异性的新型金基化合物促进线粒体功能消除 TNBC； 2）描述了已开发的TNBC抑制机制金基化合物； 3) 确定黄金抗癌药物的体内功效和药效学。至关重要的是，所产生的化合物将为 TNBC 的靶向治疗提供动力，这是一个尚未满足的目标需要。