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：
10685301
负责人：
Samuel Gorman Awuah
金额：
$ 34.14万
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/10685301
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 Mus 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 cancer cell cell growth clinical efficacy clinical subtypes comparative 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 rational design 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。黄金衍生的抗癌化合物是有希望的治疗剂疾病应用，包括癌症。三重阴性乳腺癌（TNBC）是一种积极的临床亚型缺乏有效治疗的乳腺癌。大约有66％的乳腺癌死亡与TNBC相关，因此，迫切需要务实的治疗选择。我们的研究计划旨在利用独特的空间基于黄金[Au（i）和Au（iii）]复合物作为新目标的基础的性质和化学反应性消除TNBC的治疗方案。我们已经开发了带有不同脚手架的黄金化合物库， TNBC细胞中不同的作用方式，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显示出较高的效力，对癌细胞的选择性超过30倍细胞。使用NCI-60屏幕进行比较分析证实了铅化合物的毒性，Auphos对A 包括TNBC在内的乳腺癌面板。 BALB/C小鼠的初步最大耐受剂量研究表明在动物中可以很好地耐受黄金化合物。此外，Auphos施加了深刻的抗肿瘤效应并防止转移4T1 TNBC小鼠模型中的肝转移。作用机理研究表明，黄金化合物靶向不同的线粒体过程，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针对不同线粒体和生物学的一组基于黄金的药物消除TNBC的目标。我们将通过以下目的测试该项目中的假设：目标1）优化化学和功能多样的金抗癌药；目标2）描述基于黄金的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鼠标模型中。该项目的结果将1）提供具有特异性的新型基于黄金的化合物为了消除线粒体功能； 2）描述发达的TNBC抑制机制基于黄金的化合物； 3）建立金抗癌剂的体内功效和药效学。至关重要的是，生成的化合物将为TNBC的靶向疗法提供动力，这是一种未满足的需要。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Stable Au(I) catalysts for oxidant-free C-H Functionalization with Iodoarenes.

DOI：
10.1016/j.jcat.2022.02.019
发表时间：
2022-04
期刊：
Journal of catalysis
影响因子：
7.3
作者：
Mertens RT;Greif CE;Coogle JT;Berger G;Parkin S;Watson MD;Awuah SG
通讯作者：
Awuah SG

Self-assembled ruthenium and osmium nanosystems display a potent anticancer profile by interfering with metabolic activity.

DOI：
10.1039/d2qi00423b
发表时间：
2022-06-07
期刊：
INORGANIC CHEMISTRY FRONTIERS
影响因子：
7
作者：
Marloye, Mickael;Inam, Haider;Moore, Connor J.;Mertens, Tyler R.;Ingels, Aude;Koch, Marilin;Nowicki, Michal O.;Mathieu, Veronique;Pritchard, Justin R.;Awuah, Samuel G.;Lawler, Sean E.;Meyer, Franck;Dufrasne, Francois;Berger, Gilles
通讯作者：
Berger, Gilles

A Breast Cancer Stem Active Cobalt(III)-Cyclam Complex Containing Flufenamic Acid with Immunogenic Potential.

一种乳腺癌干活性钴 (III)-仙客来复合物，含有具有免疫原性潜力的氟芬那酸。

DOI：
10.1002/anie.202317940
发表时间：
2024
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
0
作者：
Fang,Jiaxin;Orobator,OwamagbeN;Olelewe,Chibuzor;Passeri,Ginevra;Singh,Kuldip;Awuah,SamuelG;Suntharalingam,Kogularamanan
通讯作者：
Suntharalingam,Kogularamanan

The anti-breast cancer stem cell properties of gold(i)-non-steroidal anti-inflammatory drug complexes.