Harnessing MDM2‐Mediated Targeted Degradation of Transcriptional and Epigenetic Machinery to Disrupt Oncogenic Addictions in Pediatric Sarcoma

ABSTRACT Despite considerable pathological diversity, pediatric sarcomas lack molecularly targeted treatments, demanding deeper pathobiological insights and innovative therapeutic strategies. Here, we demonstrate that overexpressed MDM2 functions as an important pathogenic driver in these malignancies, rewiring oncogenic programs through both p53‐independent chromatin occupancy to regulate active transcription and conventional proteasome‐mediated p53 degradation leading to pathway suppression. To leverage this dependency for targeted eradication of pediatric sarcomas with MDM2 overexpression, we develop MDM2‐recruiting proteolysis‐targeting chimeras that selectively degrade the CDK9/Cyclin T complex (P‐TEFb). Among the lead compounds, dCDK9‐010 demonstrates superior activity compared to its parental CDK9 inhibitor or MDM2 antagonist either alone or in combination, by coordinatedly disrupting the MDM2‐p53 axis and super‐enhancer‐driven transcription. Remarkably, the transcriptional effects of P‐TEFb degradation by dCDK9‐010 are phenocopied by MDM2‐mediated BET degradation, resulting in potent anti‐sarcoma efficacy alongside a favorable therapeutic index and minimal toxicity in nonmalignant cells. Moreover, these MDM2‐recruiting transcriptional/epigenetic machinery degraders (termed MDM2‐TEMADs) consistently impair the homologous recombination repair pathway and confer synthetic lethality with PARP inhibitors. Together, this work elucidates MDM2's central role in pediatric sarcoma pathogenesis and presents dCDK9‐010 as a first‐in‐class, MDM2‐recruiting P‐TEFb degrader and an exemplary MDM2‐TEMAD that enables precise targeting of MDM2‐dependent oncogenic transcriptional addiction.