MDM2 Amplification Enables Selective PROTAC Targeting of Tumor Cells

Proteolysis-targeting chimeras (PROTAC) are bivalent molecules that simultaneously bind to proteins of interest and cellular ubiquitin E3 ligases to promote target degradation. Tumor-specific expression of E3 should increase therapeutic efficacy and reduce toxicity in cancer therapy applications. The E3 ligases currently employed during PROTAC design, such as CRBN, VHL, c-IAP, and MDM2, are ubiquitously expressed and not considered tumor-specific. However, MDM2 is part of the p53-negative feedback loop and is dynamically regulated at transcriptional and posttranslational levels. MDM2 gene amplification occurs at a frequency of 4% to 20% in multiple tumor types. To investigate whether MDM2 can serve as a tumor-specific PROTAC E3 in certain settings, we analyzed the benchmark compound A1874 (JQ1-Idasanutlin chimera targeting BRD4) under various conditions that affect MDM2 expression and activity. The results showed that A1874 activity is dependent on p53-mediated induction of MDM2 expression and is inactive in cells with mutant p53. Importantly, A1874 showed, on average, ∼12-fold higher potency in tumor cells with MDM2 amplification compared with nonamplified cells, correlating with enhanced cytotoxicity. The results suggest that tumors with MDM2 amplification or overexpression can be selectively targeted using the PROTAC approach.