ONC201-Derived Tetrahydropyridopyrimidindiones as Powerful ClpP Protease Activators to Tackle Diffuse Midline Glioma
Pediatric diffuse intrinsic pontine glioma (DIPG), classified under diffuse midline glioma, is a deadly tumor, with no effective treatments. The human mitochondrial protease <i>h</i>ClpP is a potential DIPG therapeutic target, and this study describes the synthesis of two new series of tetrahydropyridopyrimidindiones (THPPDs) as <i>h</i>ClpP activators. Among the tested compounds, we have identified <b>36</b> (THX6) that shows a strong <i>h</i>ClpP activation (EC<sub>50</sub> = 1.18 μM) and good cytotoxicity in <b>ONC201</b>-resistant cells (IC<sub>50</sub> = 0.13 μM). Studying the oxidation mechanisms on cell membranes, the treatment of DIPG cells with <b>36</b> (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 <b>36</b> (THX6) accomplishes its antitumor activity in DIPG cell lines.
Authors
- Paola Loguercio Polosa
- Luigi Mondello (ORCID: https://orcid.org/0000-0002-8890-675X)
- Domenico Armenise
- Alessandro Bonifazi (ORCID: https://orcid.org/0000-0002-7306-0114)
- Maria Grazia Perrone (ORCID: https://orcid.org/0000-0003-4195-5228)
- Antonio Scilimati (ORCID: https://orcid.org/0000-0003-2740-6425)
- Francesca Rizzo (ORCID: https://orcid.org/0000-0002-1736-8966)
- Morena Miciaccia (ORCID: https://orcid.org/0000-0002-0727-6435)
- Francesco Bruni (ORCID: https://orcid.org/0000-0001-5120-5936)
- Anna Maria Sardanelli (ORCID: https://orcid.org/0000-0002-8535-7601)
- Savina Ferorelli (ORCID: https://orcid.org/0000-0001-6686-9364)
- Gianfranco Cavallaro (ORCID: https://orcid.org/0009-0009-6759-3860)
- Antonella Cormio (ORCID: https://orcid.org/0000-0002-6029-1722)
- Giuseppe Micalizzi (ORCID: https://orcid.org/0000-0003-1073-991X)
- Cosimo G. Fortuna (ORCID: https://orcid.org/0000-0003-1889-886X)
- Denise P. Muñoz (ORCID: https://orcid.org/0000-0002-0960-6063)
- Paola Dugo (ORCID: https://orcid.org/0000-0002-9432-1782)
- Olga Maria Baldelli
- Silvana Filieri
- Anselma Liturri (ORCID: https://orcid.org/0009-0005-3291-8910)
Institutions
- University of Messina (IT)
- National Institutes of Health (US)
- National Institute on Drug Abuse (US)
- University of California, San Francisco (US)
- University of Catania (IT)
- Institut de Biosciences et Biotechnologies (FR)
- UCSF Helen Diller Family Comprehensive Cancer Center (US)
- U-M Rogel Cancer Center (US)
- University of Bari Aldo Moro (IT)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-02-20
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01723
- Citations
- 11
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 8.87
Funders
- Merck
- Shimadzu
- Ministero dell'Università e della Ricerca
- National Institute on Drug Abuse