Gold-derived therapeutic compounds for disease application

项目摘要/摘要。金衍生抗癌化合物是一种很有前途的治疗药物 疾病应用，包括癌症。三阴性乳腺癌是一种侵袭性的临床亚型。 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。我们的研究计划试图利用独特的空间 作为新靶标基础的金基[Au(I)和Au(III)]配合物的性质和化学反应活性 消除TNBC的治疗方案。我们开发了具有不同支架的金化合物文库和 在TNBC细胞中的不同作用模式，包括调节线粒体的生物发生和形态。这个 化合物在纳摩尔范围内表现出高效力，对癌细胞的选择性是正常的30倍 细胞。使用NCI-60筛查的比较分析证实了先导化合物AuPhos对A 包括TNBC在内的乳腺癌专家小组。对BALB/c小鼠的初步最大耐受量研究表明 不同类别的黄金化合物在动物身上都可以很好地耐受。此外，AuPhos还发挥了深远的作用 在转移性4T1TNBC小鼠模型中的抗肿瘤作用和防止肝转移。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，对黄金支架进行人工修饰将使 开发一套针对不同线粒体位置和生物的金基药物 旨在消除TNBC的目标。我们将通过以下目标来验证本项目中的假设：目标1)优化 化学和功能不同的金抗癌剂；目的2)阐明金基抗癌剂的作用机理 线粒体功能的调节；以及目的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 用于线粒体功能以消除TNBC；2)用已开发的 金基化合物；以及3)建立金抗癌剂的体内效力和药效学。 关键的是，产生的化合物将为TNBC的靶向治疗提供动力，而TNBC是一种未得到满足的 需要。

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.