Targeting mitochondrial protease in diffuse gliomas

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.