PROTAC-Mediated Targeted Degradation of MDM2 Induces Tumor-Suppressive Signaling in Osteosarcoma Cells.

Osteosarcoma, the most common malignant bone tumor in young individuals, often exhibits poor outcomes due to MDM2-mediated suppression of the p53 pathway. Whereas conventional MDM2 inhibitors block the p53-MDM2 interaction but frequently induce compensatory MDM2 upregulation, proteolysis-targeting chimeras (PROTACs) directly degrade MDM2 and bypass this limitation. Here, we investigated the anticancer efficacy of two MDM2-targeting PROTAC compounds, CL0144 and CL0174, in osteosarcoma models. In Saos-2 and U2OS cells, both PROTACs efficiently induced MDM2 degradation, leading to activation of p53 or p73 signaling, increased reactive oxygen species production, apoptotic cell death, and marked reductions in viability. PROTAC treatment also significantly suppressed proliferation, colony formation, sphere formation, migration, and invasion. In vivo, xenograft assays demonstrated robust tumor growth inhibition following PROTAC administration. Collectively, these findings demonstrate that MDM2-targeting PROTACs exert strong antitumor effects by degrading MDM2 and disrupting downstream oncogenic pathways, supporting their potential as a promising therapeutic strategy for osteosarcoma.