Preclinical efficacy and mechanism of action of dordaviprone in H3 K27M-mutant diffuse glioma

Abstract Imipridone dordaviprone (ONC201) is a first-in-class brain-penetrant allosteric mitochondrial caseinolytic protease P (ClpP) agonist and bitopic dopamine receptor D2/3 (DRD2/3) antagonist. Clinical trials of dordaviprone have reported durable tumor responses, clinical benefit, and tolerability in recurrent histone H3 K27M-mutant diffuse glioma pediatric and adult patients, leading to its accelerated approval by the US Food and Drug Administration in 2025. The clinical efficacy of dordaviprone in newly diagnosed H3 K27M-mutant diffuse glioma patients is currently being evaluated in the global Phase III ACTION study. We summarize the current literature for the mechanism of action and preclinical efficacy of dordaviprone in H3 K27M-mutant diffuse glioma. Dordaviprone treatment in H3 K27M-mutant diffuse glioma cells results in altered mitochondrial metabolism and morphology, activation of the integrated stress response, and apoptosis. Metabolic alterations induced by dordaviprone-mediated ClpP agonism impact histone demethylases, resulting in increased histone H3 K27 trimethyl (H3 K27me3) levels in H3 K27M-mutant diffuse glioma cells. Dordaviprone has shown efficacy in vitro in cell lines, patient-derived cells, and 3D neurosphere cultures of H3 K27M-mutant diffuse glioma. Single-agent dordaviprone inhibited tumor growth and/or improved survival in vivo in multiple H3 K27M-mutant diffuse glioma models, including intracranial, patient-derived xenografts, immune-competent, and genetically engineered mouse models.