Characterization of novel pyrazole compounds with potent anti-cancer activity

乳腺癌是最常诊断的肿瘤类型，也是癌症相关的常见原因。 全世界女性的死亡。在美国，非裔美国人（AA）和西班牙裔/拉丁裔妇女表现出 三阴性乳腺癌（TNBC）的比例高于白色或亚洲女性。此外，本发明还提供了一种方法， AA妇女有更高的死亡风险，并被诊断为TNBC。由于TNBC是一个 没有可用的分子靶点和缺乏免疫治疗的侵袭性亚型，我们已经将重点放在 我们最近的药物筛选，以确定对这些细胞有细胞毒性的化合物。使用活细胞 成像筛选试验由我的小组开发，我们最近筛选了4，600种新化合物， MDA-MB-231 TNBC系上的化合物的Chembridge DIVERset药物样文库，以及 检测到15种化合物对这些细胞具有显著的细胞毒活性。最强效的 随后对化合物（命名为P3 C的吡唑-3-碳酰肼）进行另外的评价。 癌细胞系，并发现对大多数癌细胞系具有细胞毒性。最近的一次结构搜索 P3 C的类似物导致鉴定出具有更强抗癌活性的化合物（P3C.1 比原来的活动。尽管P3 C和P3C.1对多种癌症具有相似的细胞毒活性， 细胞系，它们在一小部分细胞系上的活性也不同。我们的数据显示， 通过增加活性氧、线粒体去极化、半胱天冬酶诱导凋亡 活化、细胞膜破坏和DNA片段化。然而，我们的初步结果 表明吡唑激活不同的信号转导途径。我们的核心假设是 所鉴定的吡唑通过不同的途径诱导细胞凋亡。因此， 该项目是通过比较它们的基因来确定每种化合物的作用模式（MOA） 表达谱和对关键信号转导途径的影响。了解这些MOA 当在临床试验和药物组合治疗中测试化合物时，化合物是至关重要的。在 此外，该建议的一个重要目标是确定化合物是否减少/抑制肿瘤， 在植入人类肿瘤的小鼠中的进展，希望最终将这种基本的 研究有效的抗癌疗法，可以帮助减少癌症的健康差距。

Breast cancer is the most frequently diagnosed tumor type and a common cause of cancer-related deaths in women worldwide. In the US, African American (AA) and Hispanic/Latina women exhibit a higher proportion of Triple Negative Breast Cancer (TNBC) than White or Asian women. In addition, AA women have a higher risk of dying from, and being diagnosed with TNBC. Since TNBC is an aggressive subtype with no available molecular targets and lack of immunotherapy, we have focused our recent drug screens to identify compounds that are cytotoxic against these cells. Using a live-cell imaging screening assay developed by my group, we recently screened 4,600 novel compounds from the Chembridge DIVERset drug-like library of compounds on the MDA-MB-231 TNBC line and detected fifteen compounds with significant cytotoxic activity against these cells. The most potent of the compounds (a pyrazole-3-carbohydrazyde named P3C) was subsequently evaluated on additional cancer cell lines and found to be cytotoxic to most cancer cell lines. A recent search for structural analogues of P3C resulted in the identification of a compound (P3C.1) with stronger anti-cancer activity than the original. Although P3C and P3C.1 have similar cytotoxic activity on a variety of cancer cell lines, they also differ in activity on a small subset of cell lines. Our data indicate that they both induce apoptosis via increased reactive oxygen species, mitochondrial depolarization, caspase activation, cell membrane disruption, and DNA fragmentation. However, our preliminary results indicate that the pyrazoles activate distinct signal transduction pathways. Our central hypothesis is that the identified pyrazoles induce apoptosis via distinct pathways. Therefore, the main objective of this project is to determine the mode of action (MOA) of each compound by comparing their gene expression profiles and effects on key signal transduction pathways. Understanding the MOA of these compounds is critical when testing compounds in clinical trials and in drug combination therapy. In addition, an important goal of this proposal is to determine if the compounds reduce/inhibit tumor progression in mice implanted with human tumors with the hope of eventually translating this basic research into effective anticancer therapeutics that can help reduce cancer health disparities.