{"title":"Novel dual inhibitor targeting CDC25 and HDAC for treating triple-negative breast cancer","authors":"Bidyadhar Sethy, Richa Upadhyay, Iin Narwanti, Zih-Yao Yu, Sung-Bau Lee, Jing-Ping Liou","doi":"10.1007/s10495-024-02023-7","DOIUrl":null,"url":null,"abstract":"<div><p>Triple-negative breast cancer (TNBC) presents a significant challenge for treatment due to its aggressive nature and the lack of effective therapies. This study developed dual inhibitors against cell division cycle 25 (CDC25) and histone deacetylases (HDACs) for TNBC treatment. CDC25 phosphatases are crucial for activating cyclin-dependent kinases (CDKs), the master regulators of cell cycle progression. HDACs regulate various biological processes by deacetylating histone and non-histone proteins, affecting gene expression, chromatin structure, cell differentiation, and proliferation. Dysregulations of HDAC and CDC25 are associated with several human malignancies. We generated a group of dual inhibitors for CDC25 and HDAC by combining the molecular structures of CDC25 (quinoline-5,8-dione) and HDAC (hydroxamic acid or benzamide) pharmacophores. The newly developed compounds were evaluated against various solid-tumor, leukemia, and non-malignant breast epithelial cells. Among the synthesized compounds, <b>18A</b> emerged as a potent inhibitor, demonstrating significant cytotoxicity against TNBC cells, superior to its effects on other cancer types while sparing non-malignant cells. <b>18A</b> possessed similar HDAC inhibitory activity as MS-275 and potently suppressed CDC25 activity in vitro and the CDK1 dephosphorylation in cells. Additionally, <b>18A</b> hindered the progression of S and G<sub>2</sub>/M phases, triggered DNA damage, and induced apoptosis. These findings underscore the potential of <b>18A</b> as a targeted therapy for TNBC and warrants further preclinical development.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><img></picture></div></div></figure></div></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"29 11-12","pages":"2047 - 2073"},"PeriodicalIF":6.1000,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11550225/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Apoptosis","FirstCategoryId":"99","ListUrlMain":"https://link.springer.com/article/10.1007/s10495-024-02023-7","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Triple-negative breast cancer (TNBC) presents a significant challenge for treatment due to its aggressive nature and the lack of effective therapies. This study developed dual inhibitors against cell division cycle 25 (CDC25) and histone deacetylases (HDACs) for TNBC treatment. CDC25 phosphatases are crucial for activating cyclin-dependent kinases (CDKs), the master regulators of cell cycle progression. HDACs regulate various biological processes by deacetylating histone and non-histone proteins, affecting gene expression, chromatin structure, cell differentiation, and proliferation. Dysregulations of HDAC and CDC25 are associated with several human malignancies. We generated a group of dual inhibitors for CDC25 and HDAC by combining the molecular structures of CDC25 (quinoline-5,8-dione) and HDAC (hydroxamic acid or benzamide) pharmacophores. The newly developed compounds were evaluated against various solid-tumor, leukemia, and non-malignant breast epithelial cells. Among the synthesized compounds, 18A emerged as a potent inhibitor, demonstrating significant cytotoxicity against TNBC cells, superior to its effects on other cancer types while sparing non-malignant cells. 18A possessed similar HDAC inhibitory activity as MS-275 and potently suppressed CDC25 activity in vitro and the CDK1 dephosphorylation in cells. Additionally, 18A hindered the progression of S and G2/M phases, triggered DNA damage, and induced apoptosis. These findings underscore the potential of 18A as a targeted therapy for TNBC and warrants further preclinical development.
期刊介绍:
Apoptosis, a monthly international peer-reviewed journal, focuses on the rapid publication of innovative investigations into programmed cell death. The journal aims to stimulate research on the mechanisms and role of apoptosis in various human diseases, such as cancer, autoimmune disease, viral infection, AIDS, cardiovascular disease, neurodegenerative disorders, osteoporosis, and aging. The Editor-In-Chief acknowledges the importance of advancing clinical therapies for apoptosis-related diseases. Apoptosis considers Original Articles, Reviews, Short Communications, Letters to the Editor, and Book Reviews for publication.