Gold-derived therapeutic compounds for disease application

用于疾病应用的金衍生治疗化合物

• 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
• 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

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.

项目总结/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有关， 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靶向 消除TNBC的治疗方案。我们已经开发了具有不同支架的金化合物库， 在TNBC细胞中的独特作用模式，包括调节线粒体生物发生和形态。的 化合物在纳摩尔范围内显示出高效力， 细胞使用NCI-60筛选进行的比较分析证实了先导化合物AuPhos对 包括TNBC在内的一组乳腺癌。BALB/c小鼠的初步最大耐受剂量研究表明， 不同种类的金化合物在动物中可以很好地耐受。此外，AuPhos发挥了深刻的 在转移性4 T1 TNBC小鼠模型中，本发明的化合物具有抗肿瘤作用并预防肝转移。作用机制 研究表明，金化合物靶向不同的线粒体过程， 生物成因或形态学。我们假设，合成修饰的黄金支架将使 开发一套基于金的药物，针对不同的线粒体区域和生物学特性， 目标是消除TNBC。我们将通过以下目标来测试本项目中的假设：目标1）优化 化学和功能多样的金抗癌剂;目的2）阐明金基抗癌剂的作用机制， 目的3）确定优化的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 线粒体功能，以消除TNBC; 2）描绘TNBC抑制的机制，通过开发的 金基化合物;和3）建立金抗癌剂的体内功效和药效学。 重要的是，所产生的化合物将为TNBC的靶向治疗提供动力，这是一个未满足的需求。 需要的