Characterization of novel pyrazole compounds with potent anti-cancer activity

乳腺癌是最常被诊断的肿瘤类型，也是与癌症相关的常见病因。 全球女性死亡人数。在美国，非洲裔美国人(AA)和西班牙裔/拉丁裔女性表现出 三重阴性乳腺癌(TNBC)的比例高于白人或亚洲女性。此外, AA妇女死于TNBC和被诊断为TNBC的风险更高。由于TNBC是一种 没有可用的分子靶点和缺乏免疫治疗的侵袭性亚型，我们关注 我们最近的药物筛选是为了确定对这些细胞具有细胞毒性的化合物。使用活细胞 由我的团队开发的成像筛选实验，我们最近从 在MDA-MB-231 TNBC系上的Chembridge DIVERset类药物文库和 检测到15种对这些细胞具有显著细胞毒活性的化合物。最具威力的 这些化合物(一种名为P3C的吡唑-3-碳水解酶)随后在其他 并被发现对大多数癌细胞系具有细胞毒性。最近对Structure的搜索 P3c类似物鉴定出一种抗癌活性较强的化合物(P3C.1) 比原来的活跃度高。尽管P3C和P3C.1对多种癌症具有相似的细胞毒活性 除了细胞系外，它们在一小部分细胞系上的活性也不同。我们的数据表明，他们都 通过增加活性氧、线粒体去极化、半胱氨酸氨基转移酶诱导细胞凋亡 激活、细胞膜破裂和DNA断裂。然而，我们的初步结果 表明吡唑类化合物激活了不同的信号转导通路。我们的中心假设是 已鉴定的吡唑类化合物通过不同的途径诱导细胞凋亡。因此，主要目标是 这个项目是通过比较每种化合物的基因来确定它们的作用模式 表达谱及其对关键信号转导通路的影响。了解这些产品的MOA 在临床试验和药物联合治疗中测试化合物时，化合物是至关重要的。在……里面 此外，这项提案的一个重要目标是确定这些化合物是否能减少/抑制肿瘤 在植入人类肿瘤的小鼠中的进展，希望最终将这一基本的 研究有效的抗癌疗法，以帮助缩小癌症健康差距。

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.