Mouse double minute 2 homolog (MDM2) (MDM2)

Mouse double minute 2 homolog (MDM2) is a nuclear-localized E3 ubiquitin ligase that serves as the primary negative regulator of the p53 tumor suppressor (UniProt: P22301). It functions by binding to the N-terminal transactivation domain of p53, inhibiting its transcriptional activity, and mediating its ubiquitination and subsequent proteasomal degradation (PubMed: 25210018). In various malignancies, particularly soft tissue sarcomas and certain leukemias, MDM2 is frequently overexpressed or amplified, which leads to the functional inactivation of wild-type p53 and promotes oncogenesis (PubMed: 33168643). Milademetan (DS-3032) is an orally bioavailable, small-molecule inhibitor designed to occupy the p53-binding hydrophobic pocket of MDM2 (PubChem CID: 71587160). By competitively inhibiting the MDM2-p53 interaction, milademetan stabilizes p53, allowing it to accumulate and trigger downstream pathways for cell cycle arrest, senescence, and apoptosis in TP53-wild-type cancer cells (PubMed: 32451310). The input provided, "Milademetan pharmacokinetics," refers to the pharmacological properties of the drug rather than the biological target itself.

Other names

E3 ubiquitin-protein ligase Mdm2Double minute 2 proteinOncoprotein MDM2hMDM2MDM2 proto-oncogene

Inhibition of the MDM2-p53 protein-protein interaction, preventing p53 degradation and restoring p53-mediated tumor suppression (PubMed: 32451310).