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

## TL;DR

This study shows that using PROTACs to degrade MDM2 can trigger tumor-suppressing signals and reduce cancer cell growth in osteosarcoma.

## Contribution

The novel contribution is demonstrating that MDM2-targeting PROTACs bypass compensatory upregulation and induce antitumor effects in osteosarcoma models.

## Key findings

- PROTACs CL0144 and CL0174 efficiently degrade MDM2 and activate p53/p73 signaling in osteosarcoma cells.
- PROTAC treatment reduces cell viability, proliferation, and tumor growth in xenograft models.
- MDM2 degradation leads to increased apoptosis and suppression of migration and invasion in osteosarcoma cells.

## Abstract

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.