ONC201-Derived Tetrahydropyridopyrimidindiones as Powerful ClpP Protease Activators to Tackle Diffuse Midline Glioma

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.