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

The MDM2-p53 protein-protein interaction interface is a critical regulatory node in the cell cycle and tumor suppression. Mouse double minute 2 homolog (MDM2) acts as the primary negative regulator of the Tumor protein p53 (p53) by binding to its N-terminal transactivation domain, which inhibits p53-mediated transcription and targets it for ubiquitin-dependent proteasomal degradation [1, 2]. In many human cancers, particularly those where the TP53 gene remains wild-type, MDM2 is frequently overexpressed or amplified, leading to the functional inactivation of p53 and allowing for uncontrolled cell proliferation [3]. Therapeutic strategies targeting this interface involve small molecules, such as Nutlins and their clinical-grade derivatives, which occupy the hydrophobic pocket of MDM2 to prevent p53 binding [4]. By disrupting this interaction, these drugs stabilize p53, allowing it to accumulate and activate downstream targets involved in cell cycle arrest, DNA repair, and apoptosis [2, 5]. Clinical development of MDM2 inhibitors focuses primarily on TP53 wild-type tumors, though challenges such as hematologic toxicities and the potential for emergent p53 mutations remain significant hurdles [5, 6]. Sources: [1] UniProt (P22301, P04637); [2] PubMed (PMID: 25104363); [3] PubMed (PMID: 14704432); [4] PubMed (PMID: 33067318); [5] NIH/NCI Drug Dictionary (Idasanutlin); [6] PubMed (PMID: 28841434).

Other names

MDM2-p53 complexHDM2-p53 interactionMDM2-p53 binding site

Small molecule inhibition of the MDM2-p53 protein-protein interaction, which prevents MDM2-mediated ubiquitination and degradation of p53, thereby restoring p53-mediated tumor suppression and inducing apoptosis in TP53 wild-type cells.