TY - JOUR
T1 - ONC201-Derived Tetrahydropyridopyrimidindiones as Powerful ClpP Protease Activators to Tackle Diffuse Midline Glioma
AU - Miciaccia, Morena
AU - Baldelli, Olga Maria
AU - Fortuna, Cosimo G.
AU - Cavallaro, Gianfranco
AU - Armenise, Domenico
AU - Liturri, Anselma
AU - Ferorelli, Savina
AU - Muñoz, Denise P.
AU - Bonifazi, Alessandro
AU - Rizzo, Francesca
AU - Cormio, Antonella
AU - Filieri, Silvana
AU - Micalizzi, Giuseppe
AU - Dugo, Paola
AU - Mondello, Luigi
AU - Sardanelli, Anna Maria
AU - Bruni, Francesco
AU - Loguercio Polosa, Paola
AU - Perrone, Maria Grazia
AU - Scilimati, Antonio
N1 - Publisher Copyright:
© 2025 American Chemical Society.
PY - 2025/3/13
Y1 - 2025/3/13
N2 - Pediatric diffuse intrinsic pontine glioma (DIPG), classified under diffuse midline glioma, is a deadly tumor, with no effective treatments. The human mitochondrial protease hClpP is a potential DIPG therapeutic target, and this study describes the synthesis of two new series of tetrahydropyridopyrimidindiones (THPPDs) as hClpP activators. Among the tested compounds, we have identified 36 (THX6) that shows a strong hClpP activation (EC50 = 1.18 μM) and good cytotoxicity in ONC201-resistant cells (IC50 = 0.13 μM). Studying the oxidation mechanisms on cell membranes, the treatment of DIPG cells with 36 (THX6) causes a change in levels of fatty acids (PUFAs, MUFAs, and SFAs) compared to untreated cells and dysregulates the level of proteins involved in oxidative phosphorylation, biogenesis, and mitophagy that lead to a global collapse of mitochondrial integrity and function suggesting this as the mechanism through which 36 (THX6) accomplishes its antitumor activity in DIPG cell lines.
AB - Pediatric diffuse intrinsic pontine glioma (DIPG), classified under diffuse midline glioma, is a deadly tumor, with no effective treatments. The human mitochondrial protease hClpP is a potential DIPG therapeutic target, and this study describes the synthesis of two new series of tetrahydropyridopyrimidindiones (THPPDs) as hClpP activators. Among the tested compounds, we have identified 36 (THX6) that shows a strong hClpP activation (EC50 = 1.18 μM) and good cytotoxicity in ONC201-resistant cells (IC50 = 0.13 μM). Studying the oxidation mechanisms on cell membranes, the treatment of DIPG cells with 36 (THX6) causes a change in levels of fatty acids (PUFAs, MUFAs, and SFAs) compared to untreated cells and dysregulates the level of proteins involved in oxidative phosphorylation, biogenesis, and mitophagy that lead to a global collapse of mitochondrial integrity and function suggesting this as the mechanism through which 36 (THX6) accomplishes its antitumor activity in DIPG cell lines.
UR - https://www.scopus.com/pages/publications/85218087707
UR - https://www.scopus.com/pages/publications/85218087707#tab=citedBy
U2 - 10.1021/acs.jmedchem.4c01723
DO - 10.1021/acs.jmedchem.4c01723
M3 - Article
C2 - 39973170
AN - SCOPUS:85218087707
SN - 0022-2623
VL - 68
SP - 5190
EP - 5210
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 5
ER -