ONC201-Derived Tetrahydropyridopyrimidindiones as Powerful ClpP Protease Activators to Tackle Diffuse Midline Glioma.

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-02-20 DOI:10.1021/acs.jmedchem.4c01723

Morena Miciaccia, Olga Maria Baldelli, Cosimo G Fortuna, Gianfranco Cavallaro, Domenico Armenise, Anselma Liturri, Savina Ferorelli, Denise P Muñoz, Alessandro Bonifazi, Francesca Rizzo, Antonella Cormio, Silvana Filieri, Giuseppe Micalizzi, Paola Dugo, Luigi Mondello, Anna Maria Sardanelli, Francesco Bruni, Paola Loguercio Polosa, Maria Grazia Perrone, Antonio Scilimati

{"title":"ONC201-Derived Tetrahydropyridopyrimidindiones as Powerful ClpP Protease Activators to Tackle Diffuse Midline Glioma.","authors":"Morena Miciaccia, Olga Maria Baldelli, Cosimo G Fortuna, Gianfranco Cavallaro, Domenico Armenise, Anselma Liturri, Savina Ferorelli, Denise P Muñoz, Alessandro Bonifazi, Francesca Rizzo, Antonella Cormio, Silvana Filieri, Giuseppe Micalizzi, Paola Dugo, Luigi Mondello, Anna Maria Sardanelli, Francesco Bruni, Paola Loguercio Polosa, Maria Grazia Perrone, Antonio Scilimati","doi":"10.1021/acs.jmedchem.4c01723","DOIUrl":null,"url":null,"abstract":"Pediatric diffuse intrinsic pontine glioma (DIPG), classified under diffuse midline glioma, is a deadly tumor, with no effective treatments. The human mitochondrial protease hClpP is a potential DIPG therapeutic target, and this study describes the synthesis of two new series of tetrahydropyridopyrimidindiones (THPPDs) as hClpP activators. Among the tested compounds, we have identified 36 (THX6) that shows a strong hClpP activation (EC50 = 1.18 μM) and good cytotoxicity in ONC201-resistant cells (IC50 = 0.13 μM). Studying the oxidation mechanisms on cell membranes, the treatment of DIPG cells with 36 (THX6) causes a change in levels of fatty acids (PUFAs, MUFAs, and SFAs) compared to untreated cells and dysregulates the level of proteins involved in oxidative phosphorylation, biogenesis, and mitophagy that lead to a global collapse of mitochondrial integrity and function suggesting this as the mechanism through which 36 (THX6) accomplishes its antitumor activity in DIPG cell lines.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8000,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acs.jmedchem.4c01723","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

Pediatric diffuse intrinsic pontine glioma (DIPG), classified under diffuse midline glioma, is a deadly tumor, with no effective treatments. The human mitochondrial protease hClpP is a potential DIPG therapeutic target, and this study describes the synthesis of two new series of tetrahydropyridopyrimidindiones (THPPDs) as hClpP activators. Among the tested compounds, we have identified 36 (THX6) that shows a strong hClpP activation (EC₅₀ = 1.18 μM) and good cytotoxicity in ONC201-resistant cells (IC₅₀ = 0.13 μM). Studying the oxidation mechanisms on cell membranes, the treatment of DIPG cells with 36 (THX6) causes a change in levels of fatty acids (PUFAs, MUFAs, and SFAs) compared to untreated cells and dysregulates the level of proteins involved in oxidative phosphorylation, biogenesis, and mitophagy that lead to a global collapse of mitochondrial integrity and function suggesting this as the mechanism through which 36 (THX6) accomplishes its antitumor activity in DIPG cell lines.

查看原文本刊更多论文

求助全文

约1分钟内获得全文求助全文

来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.