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

Morena Miciaccia1, Olga Maria Baldelli1, Cosimo G Fortuna2

  • 1Research Laboratory for Woman and Child Health, Department of Pharmacy─Pharmaceutical Sciences, University of Bari Aldo Moro, 70125 Bari, Italy.

Journal of Medicinal Chemistry
|February 20, 2025
PubMed

Insights

Researchers developed new compounds to activate the human mitochondrial protease hClpP, a target for diffuse midline glioma. Compound 36 (THX6) shows potent hClpP activation and kills DIPG cells by disrupting mitochondrial function.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brain tumor with limited treatment options.
  • The human mitochondrial protease hClpP is a potential therapeutic target for DIPG.
  • Developing novel activators of hClpP is crucial for advancing DIPG treatment strategies.

Purpose of the Study:

  • To synthesize and evaluate new series of tetrahydropyridopyrimidindiones (THPPDs) as activators of hClpP.
  • To identify potent hClpP activators with significant cytotoxicity against DIPG cells, including those resistant to existing therapies.
  • To elucidate the mechanism of action of the identified compounds in DIPG cells.

Main Methods:

  • Synthesis of two novel series of tetrahydropyridopyrimidindiones (THPPDs).
  • Assay of hClpP activation and cytotoxicity in DIPG cell lines.
  • Analysis of fatty acid profiles and protein levels related to mitochondrial function (oxidative phosphorylation, biogenesis, mitophagy).

Main Results:

  • Compound 36 (THX6) demonstrated strong hClpP activation (EC50 = 1.18 μM).
  • Compound 36 exhibited significant cytotoxicity in ONC201-resistant DIPG cells (IC50 = 0.13 μM).
  • Treatment with 36 altered fatty acid levels and dysregulated mitochondrial proteins, leading to mitochondrial dysfunction.

Conclusions:

  • Compound 36 (THX6) is a promising hClpP activator with potent antitumor activity against DIPG cells.
  • The antitumor effects of 36 are mediated by the disruption of mitochondrial integrity and function.
  • These findings suggest THPPDs as a potential therapeutic strategy for DIPG.

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