H3K27-altered diffuse midline glioma (DMG) is one of the most aggressive pediatric brain tumors, with a median overall survival of less than 12 months. Radiotherapy treatment (RT) provides a transient clinical response, with an increasing average survival of approximately 3 months. Given that the tumor often recurs within few months after RT, there is a strong need for targeted therapeutic strategies that directly address the H3K27-alterations.1 One promising drug under study is Dordaviprone, which API is ONC201, a brain penetrant compound belonging to imipridone family (NCT02525692).2 Nonetheless, despite initial clinical promise, ONC201 has shown limited efficacy in patients, underscoring the need to identify alternative molecules.2 More recent studies have identified the target of ONC201, being a potent activator of the human mitochondrial serin-protease ClpP. Together with ClpX, ClpP is involved in the degradation of mitochondrial respiratory chain proteins, thereby disrupting energy homeostasis. When abnormally activated by small molecules, ClpP triggers uncontrolled degradation of essential mitochondrial proteins, leading to mitochondrial failure, metabolic collapse, and ultimately cell death. This mechanism is particularly effective in tumor cells that are highly dependent on mitochondrial function, making ClpP hyperactivation an attractive anti-tumor strategy (Fig. 1).3 To enhance the efficacy of ONC201 and ClpP activation, we developed a series of its structurally simplified derivatives, representing the molecular evolution of ClpP activators. These novel molecules retain high target selectivity for ClpP, exhibit stronger mitochondrial protease activation, resulting in potent degradation of mitochondrial matrix and consequent collapse of oxidative phosphorylation. This ClpP-dependent disruption of mitochondrial function represents a potent anti-cancer mechanism, particularly relevant for tumors with high mitochondrial reliance.
TARGETING HUMAN MITOCHONDRIAL ClpP AS A NOVEL THERAPEUTIC APPROACH TO H3K27-ALTERED DIFFUSE MIDLINE GLIOMA
Morena Miciaccia;Olga Maria BaldelliMembro del Collaboration Group
;Anselma LiturriMembro del Collaboration Group
;Francesco BruniMembro del Collaboration Group
;Paola Loguercio PolosaMembro del Collaboration Group
;Savina FerorelliMembro del Collaboration Group
;Maria Grazia PerroneMembro del Collaboration Group
;Antonio ScilimatiMembro del Collaboration Group
2025-01-01
Abstract
H3K27-altered diffuse midline glioma (DMG) is one of the most aggressive pediatric brain tumors, with a median overall survival of less than 12 months. Radiotherapy treatment (RT) provides a transient clinical response, with an increasing average survival of approximately 3 months. Given that the tumor often recurs within few months after RT, there is a strong need for targeted therapeutic strategies that directly address the H3K27-alterations.1 One promising drug under study is Dordaviprone, which API is ONC201, a brain penetrant compound belonging to imipridone family (NCT02525692).2 Nonetheless, despite initial clinical promise, ONC201 has shown limited efficacy in patients, underscoring the need to identify alternative molecules.2 More recent studies have identified the target of ONC201, being a potent activator of the human mitochondrial serin-protease ClpP. Together with ClpX, ClpP is involved in the degradation of mitochondrial respiratory chain proteins, thereby disrupting energy homeostasis. When abnormally activated by small molecules, ClpP triggers uncontrolled degradation of essential mitochondrial proteins, leading to mitochondrial failure, metabolic collapse, and ultimately cell death. This mechanism is particularly effective in tumor cells that are highly dependent on mitochondrial function, making ClpP hyperactivation an attractive anti-tumor strategy (Fig. 1).3 To enhance the efficacy of ONC201 and ClpP activation, we developed a series of its structurally simplified derivatives, representing the molecular evolution of ClpP activators. These novel molecules retain high target selectivity for ClpP, exhibit stronger mitochondrial protease activation, resulting in potent degradation of mitochondrial matrix and consequent collapse of oxidative phosphorylation. This ClpP-dependent disruption of mitochondrial function represents a potent anti-cancer mechanism, particularly relevant for tumors with high mitochondrial reliance.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
