Characterization of novel pyrazole compounds with potent anti-cancer activity

具有有效抗癌活性的新型吡唑化合物的表征

基本信息

批准号：
10627543
负责人：
RENATO J AGUILERA
金额：
$ 15.14万
依托单位：
UNIVERSITY OF TEXAS EL PASO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10627543
关键词：
Affect African American Animals Antibodies Antineoplastic Agents Asian BCL1 Oncogene Basic Science Biochemical Biological Assay Breast Breast Cancer Cell Breast Cancer cell line CASP3 gene Cancer Etiology Cancer cell line Caspase Cause of Death Cell Death Induction Cell Line Cell membrane Cells Cessation of life Clinical Trials Combination Drug Therapy Country DNA Fragmentation Data Databases Diagnosis Docking Drug Screening Exhibits FDA approved Family Future Gene Expression Gene Expression Profile Gene Expression Profiling Genes Goals Hispanic Human Hypoxia Immunotherapy Implant Induction of Apoptosis Latina Leukemic Cell Libraries Luc Gene Luciferases MDA MB 231 Malignant Neoplasms Minority Groups Mitochondria Molecular Target Monitor Mus Names Network-based Pathway interactions Pharmaceutical Preparations Pharmacotherapy Phosphorylation Phosphotransferases Protein Kinase Proteins Pyrazoles Reactive Oxygen Species Reverse Transcriptase Polymerase Chain Reaction Role Signal Transduction Signal Transduction Pathway Small Interfering RNA Testing Therapeutic Agents Translating Tumor Suppressor Genes United States National Institutes of Health Western Blotting Woman Xenograft Model analog anti-cancer anti-cancer therapeutic anticancer activity bioluminescence imaging cancer cell cancer health disparity cancer type cytotoxic differential expression effective therapy experimental study high risk in silico in vivo inhibitor kinase inhibitor knock-down leukemia live cell imaging malignant breast neoplasm novel novel anticancer drug screening stable cell line timeline transcriptome transcriptome sequencing transcriptomic profiling triple-negative invasive breast carcinoma tumor tumor diagnosis tumor growth tumor progression

Affect African American Animals Antibodies Antineoplastic Agents Asian BCL1 Oncogene Basic Science Biochemical Biological Assay Breast Breast Cancer Cell Breast Cancer cell line CASP3 gene Cancer Etiology Cancer cell line Caspase Cause of Death Cell Death Induction Cell Line Cell membrane Cells Cessation of life Clinical Trials Combination Drug Therapy Country DNA Fragmentation Data Databases Diagnosis Docking Drug Screening Exhibits FDA approved Family Future Gene Expression Gene Expression Profile Gene Expression Profiling Genes Goals Hispanic Human Hypoxia Immunotherapy Implant Induction of Apoptosis Latina Leukemic Cell Libraries Luc Gene Luciferases MDA MB 231 Malignant Neoplasms Minority Groups Mitochondria Molecular Target Monitor Mus Names Network-based Pathway interactions Pharmaceutical Preparations Pharmacotherapy Phosphorylation Phosphotransferases Protein Kinase Proteins Pyrazoles Reactive Oxygen Species Reverse Transcriptase Polymerase Chain Reaction Role Signal Transduction Signal Transduction Pathway Small Interfering RNA Testing Therapeutic Agents Translating Tumor Suppressor Genes United States National Institutes of Health Western Blotting Woman Xenograft Model analog anti-cancer anti-cancer therapeutic anticancer activity bioluminescence imaging cancer cell cancer health disparity cancer type cytotoxic differential expression effective therapy experimental study high risk in silico in vivo inhibitor kinase inhibitor knock-down leukemia live cell imaging malignant breast neoplasm novel novel anticancer drug screening stable cell line timeline transcriptome transcriptome sequencing transcriptomic profiling triple-negative invasive breast carcinoma tumor tumor diagnosis tumor growth tumor progression

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项目摘要

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.

乳腺癌是最常见的肿瘤类型，也是癌症相关的常见原因全世界女性死亡。在美国，非裔美国人（AA）和西班牙裔/拉丁裔妇女展示三重阴性乳腺癌（TNBC）的比例高于白人或亚洲妇女。此外， AA妇女死于死亡并被诊断出患有TNBC的风险更高。由于TNBC是积极的亚型没有可用的分子靶标，缺乏免疫疗法，我们已经集中了我们最近的药物筛选以鉴定针对这些细胞的细胞毒性的化合物。使用活细胞我小组开发的成像筛选测定法，我们最近筛选了4,600种新型化合物 MDA-MB-231 TNBC系列上的Chembridge Diverset药物样库和检测到15种对这些细胞具有显着细胞毒性活性的化合物。最有效的随后对化合物（吡唑-3-碳水化合物p3C）进行了评估癌细胞系，发现大多数癌细胞系具有细胞毒性。最近搜索结构 P3C的类似物导致鉴定具有更强抗癌的化合物（P3C.1）活动比原始活动。尽管P3C和P3C.1对多种癌症具有相似的细胞毒性活性细胞系，它们的活性在一小部分细胞系上也有所不同。我们的数据表明他们俩通过增加的活性氧，线粒体去极化，caspase诱导凋亡激活，细胞膜破坏和DNA碎片。但是，我们的初步结果表明吡唑激活不同的信号转导途径。我们的中心假设是确定的吡唑通过不同的途径诱导凋亡。因此，主要目标该项目是通过比较其基因来确定每种化合物的作用方式（MOA）表达曲线和对钥匙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疗法中测试化合物时，化合物至关重要。在此外，该提案的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进展，希望最终翻译这种基本研究有效的抗癌治疗剂，可以帮助减少癌症健康差异。