Related Experiment Video
Updated: Jul 15, 2026
Preparation Of Neovascular Tissues from Human Glioma Tissues for Quantitative Proteomics Analysis of Tumor Angiogenesis
Published on: March 20, 2026
Targeting mitochondrial protease in diffuse gliomas
Olga Kim1, Jinkyu Jung2, Shaunak Sathe2
1National Cancer Institute Bethesda, Maryland United States.
Abstract:
Caseinolytic protease proteolytic subunit (ClpP) is part of the mitochondrial ClpXP protease responsible for degrading damaged proteins in the matrix, thus maintaining metabolic homeostasis. Small molecule activators of ClpP (ClpP agonists) have recently shown great promise against metabolically active cancers. TR107, a novel ClpP activator, demonstrates potent and selective cytotoxicity against glioma cells at nanomolar concentrations. Compared to the FDA-approved ClpP agonist ONC201 (Dordaviprone), TR107 shows greater efficacy across patient-derived and isogenic glioma models. TR107 effects are ClpP-dependent and result in widespread mitochondrial dysfunction evident by extensive protein degradation, impaired OxPhos, reduced mtDNA copy number, and ATP depletion. These disruptions are more severe in IDH-mutant than IDH-wildtype glioma cells, leading to enhanced cell cycle arrest, apoptosis, and inhibition of mTOR/AKT/4EBP1 signaling pathway. In this study, we show that ClpP agonism demonstrates preferential anti-tumor activity against IDH-mutant glioma in in vitro, ex vivo, and in vivo models. These findings support TR107 as a promising new targeted therapeutic for IDH-mutant gliomas.
Insights
A new drug, TR107, effectively targets glioma cells by activating caseinolytic protease (ClpP), leading to mitochondrial dysfunction. This ClpP activator shows particular promise for treating IDH-mutant gliomas.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- The mitochondrial ClpXP protease, including caseinolytic protease (ClpP), degrades damaged proteins to maintain cellular homeostasis.
- Small molecule activators of ClpP (ClpP agonists) are emerging as potential therapeutics for metabolically active cancers.
Purpose of the Study:
- To evaluate the efficacy and mechanism of TR107, a novel ClpP activator, against glioma cells.
- To compare TR107 with the FDA-approved ClpP agonist ONC201.
- To investigate the preferential activity of TR107 against IDH-mutant gliomas.
Main Methods:
- In vitro, ex vivo, and in vivo studies using patient-derived and isogenic glioma models.
- Assessment of TR107 cytotoxicity, ClpP-dependency, and mitochondrial function (protein degradation, oxidative phosphorylation, mtDNA copy number, ATP levels).
- Analysis of cell cycle arrest, apoptosis, and signaling pathways (mTOR/AKT/4EBP1).
Main Results:
- TR107 demonstrated potent and selective cytotoxicity against glioma cells at nanomolar concentrations.
- TR107 induced ClpP-dependent mitochondrial dysfunction, including protein degradation, impaired OxPhos, reduced mtDNA, and ATP depletion.
- TR107 exhibited greater efficacy than ONC201 and showed preferential anti-tumor activity in IDH-mutant glioma models.
Conclusions:
- TR107 is a potent ClpP activator with significant anti-glioma activity.
- TR107 induces severe mitochondrial dysfunction, particularly in IDH-mutant glioma cells.
- TR107 represents a promising targeted therapeutic candidate for IDH-mutant gliomas.
