ONC201-Derived Tetrahydropyridopyrimidindiones as Powerful ClpP Protease Activators to Tackle Diffuse Midline Glioma
Morena Miciaccia, Olga Maria Baldelli, Cosimo G. Fortuna, Gianfranco Cavallaro, Domenico Armenise, Anselma Liturri, Savina Ferorelli, Denise P. Muñoz, Alessandro Bonifazi, Francesca Rizzo, Antonella Cormio, Silvana Filieri, Giuseppe Micalizzi, Paola Dugo, Luigi Mondello, Anna Maria Sardanelli, Francesco Bruni, Paola Loguercio Polosa, Maria Grazia Perrone, Antonio Scilimati
Abstract
Pediatric diffuse intrinsic pontine glioma (DIPG), classified under diffuse midline glioma, is a deadly tumor, with no effective treatments. The human mitochondrial protease h ClpP is a potential DIPG therapeutic target, and this study describes the synthesis of two new series of tetrahydropyridopyrimidindiones (THPPDs) as h ClpP activators. Among the tested compounds, we have identified 36 (THX6) that shows a strong h ClpP activation (EC 50 = 1.18 μM) and good cytotoxicity in ONC201 -resistant cells (IC 50 = 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.