Mouse double minute 2 homolog–Tumor protein p53 protein-protein interface (MDM2–p53 PPI)

The MDM2–p53 protein-protein interface is a critical regulatory node in cellular homeostasis, governing the activity of the tumor suppressor p53. Under normal conditions, the E3 ubiquitin ligase MDM2 (Mouse double minute 2 homolog) binds to the N-terminal transactivation domain of p53, promoting its ubiquitination and subsequent proteasomal degradation, while also directly inhibiting its transcriptional activity [UniProt: P22301, P04637]. In many cancers, particularly those retaining wild-type TP53, MDM2 is frequently overexpressed or amplified, leading to the constitutive inactivation of p53 and facilitating uncontrolled cell proliferation and survival [PubMed: 25213910]. Therapeutic strategies targeting this interface involve small-molecule inhibitors, often referred to as MDM2 antagonists, which occupy the hydrophobic p53-binding pocket on MDM2. By sterically hindering the interaction, these drugs stabilize p53, allowing it to accumulate and activate downstream target genes involved in cell cycle arrest, DNA repair, and apoptosis [PubMed: 14703334]. Clinical development of these inhibitors focuses on TP53 wild-type tumors, such as dedifferentiated liposarcoma and certain leukemias, though challenges remain regarding hematological toxicities and the emergence of resistance through p53 mutations [PubMed: 33075111].

Other names

MDM2-p53 interactionMDM2-TP53 interfaceHDM2-p53 interfacep53-MDM2 binding site

Small-molecule inhibition of the MDM2-p53 interaction by binding to the p53-binding pocket of MDM2, preventing p53 degradation and restoring its tumor-suppressive activity [PubMed: 14703334, 25213910].