Characterization of novel pyrazole compounds with potent anti-cancer activity

乳腺癌是最常诊断的肿瘤类型，也是癌症相关疾病的常见原因 全球女性死亡人数。在美国，非裔美国人 (AA) 和西班牙裔/拉丁裔女性表现出 三阴性乳腺癌 (TNBC) 的比例高于白人或亚洲女性。此外， AA 女性死于 TNBC 和被诊断为 TNBC 的风险更高。由于 TNBC 是 侵袭性亚型没有可用的分子靶点并且缺乏免疫治疗，我们重点关注 我们最近进行了药物筛选，以确定对这些细胞具有细胞毒性的化合物。使用活细胞 我的团队开发的成像筛选方法，我们最近从其中筛选了 4,600 种新化合物 MDA-MB-231 TNBC 系列上的 Chembridge DIVERset 类药物化合物库以及 检测到十五种对这些细胞具有显着细胞毒活性的化合物。其中最有力的 随后对这些化合物（一种名为 P3C 的吡唑-3-碳酰肼）进行了额外的评估 癌细胞系，并发现对大多数癌细胞系具有细胞毒性。最近对结构的探索 P3C的类似物导致鉴定出具有更强抗癌作用的化合物（P3C.1） 活性比原来高。尽管P3C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有所不同。我们的数据表明他们都 通过增加活性氧、线粒体去极化、半胱天冬酶诱导细胞凋亡 激活、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。我们的中心假设是 所鉴定的吡唑通过不同的途径诱导细胞凋亡。因此，主要目标是 该项目是通过比较每种化合物的基因来确定其作用模式 (MOA) 表达谱和对关键信号转导途径的影响。了解这些的 MOA 在临床试验和药物联合治疗中测试化合物时，化合物至关重要。在 此外，该提案的一个重要目标是确定这些化合物是否可以减少/抑制肿瘤 在植入人类肿瘤的小鼠中取得进展，希望最终能够转化这一基本原理 研究有效的抗癌疗法，有助于减少癌症健康差异。

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.