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MDM2 is the protein that degrades p53; blocking it reactivates p53 in tumours where the gene is intact, especially the liposarcomas that carry extra copies of MDM2.
MDM2 is an E3 ubiquitin ligase and p53's principal negative regulator; MDM2 amplification defines well-differentiated/dedifferentiated liposarcoma (>90%), intimal sarcoma and low-grade osteosarcoma, and occurs in ~5% of glioblastoma and some breast and lung cancers. MDM2-p53 inhibitors (nutlins: idasanutlin, milademetan, brigimadlin, navtemadlin, siremadlin, alrizomadlin) reactivate wild-type p53 but cause on-target thrombocytopenia and GI toxicity and select for TP53 mutations. Brigimadlin (Brightline-1, dedifferentiated liposarcoma vs doxorubicin) is the lead phase 3; navtemadlin is in phase 3 in myelofibrosis after ruxolitinib (BOREAS). Idasanutlin failed in AML (MIRROS). MDM2 amplification also predicts hyperprogression on checkpoint inhibitors.
In plain words · MDM2 is the protein that degrades p53; blocking it reactivates p53 in tumours where the gene is intact, especially the liposarcomas that carry extra copies of MDM2.
MDM2 is the protein that degrades p53; blocking it reactivates p53 in tumours where the gene is intact, especially the liposarcomas that carry extra copies of MDM2.
RING-domain E3 ligase that binds the p53 transactivation domain, ubiquitinates it for proteasomal degradation and exports it from the nucleus; p53 in turn transcribes MDM2 (negative feedback); MDMX (MDM4) is a heterodimer partner.
2 products aim at MDM2: small molecules. Drugs bind the molecule precisely: to switch it off, flag the cell for the immune system, or deliver a payload.
Broadly expressed or essential: HPA lists MDM2 among essential proteins and finds the RNA at low tissue specificity; the 2 medicines aimed at it (KRT-232, Brigimadlin) act on the wild-type protein, so normal tissue is exposed and the therapeutic window comes from the tumour's faster division or its dependence on the protein. HPA MDM2: RNA low tissue specificity; high antibody staining in 45 normal tissues; highest cancer staining breast cancer (12 of 12 high). Distribution: 5 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Sarcomas (soft tissue, bone, GIST), Biliary tract cancer (all types), Brain and spinal cord tumours (all types), Leukaemia, Myeloid neoplasms); Open Targets associates it with 0 specific cancer types at or above 0.5. (Rule 7 of scripts/fetch-target-specificity.ts.)
Sources: Human Protein Atlas MDM2 tissue; Open Targets ENSG00000135679 associations
First described 1992. Earliest sequence paper UniProt cites for the protein: Oliner J.D. et al, Nature, 1992, "Amplification of a gene encoding a p53-associated protein in human sarcomas". Source.
RING-domain E3 ligase that binds the p53 transactivation domain, ubiquitinates it for proteasomal degradation and exports it from the nucleus; p53 in turn transcribes MDM2 (negative feedback); MDMX (MDM4) is a heterodimer partner.
RNA: low tissue specificity, detected in all normal tissues.
HPA MDM2 tissue · HPA MDM2 pathology · HPA protein class: Essential proteins
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Sarcomas | 90% | MDM2 amplification in well/dedifferentiated liposarcoma | doi.org | |
| Gallbladder cancer | 12% | Amplification | Amplification in 29 of 244 samples, 11.9%, in cBioPortal gbc_mskcc_2022 and 12 of 103, 11.7%, in gbc_msk_2018; 6.5% across 1,254 biliary tract cancers of all sites (Cowzer 2026). | cBioPortal (TCGA) |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Brigimadlin is a tablet that frees the p53 'guardian' protein from MDM2, the protein that liposarcomas make in excess to keep p53 switched off. It is being compared with doxorubicin as first treatment for dedifferentiated liposarcoma in a phase 2/3 trial.
KRT-232 is an experimental small-molecule drug from Kartos Therapeutics in phase 2 trials for myeloproliferative neoplasms, diffuse large B-cell lymphoma and chronic lymphocytic leukaemia, aimed at MDM2 and TP53.
For gallbladder cancer the points that matter are that HER2 can disappear under HER2-directed pressure, that SMAD4 co-mutation predicts a worse response, and that sequencing at progression, not just at diagnosis, may be needed to guide the next line.
One target page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
This paper is the reason TP53 status, MDM2 amplification and CDKN2A loss are read together in tumour genomes. It frames the current drug development around MDM2 inhibitors and mutant p53 reactivators as attempts to restore a network rather than a single protein.
This review fixed the picture of p53 as the guardian of the genome that every textbook uses. It explains why TP53-mutant cancers are aggressive and hard to treat, why MDM2 inhibitors are being developed to reactivate wild-type p53, and why germline TP53 testing matters in families.
Query for this target: (TITLE:"MDM2" OR ABSTRACT:"MDM2") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about MDM2, not a curated reading list.
Shares Levine 1997: p53, the cellular gatekeeper for growth and division, Vogelstein, Lane and Levine 2000: surfing the p53 network, TP53-mutated (p53-abnormal), TP53.
Shares Levine 1997: p53, the cellular gatekeeper for growth and division, TP53-mutated (p53-abnormal), The p53 network (guardian of the genome), TP53.
Shares Brigimadlin, Boehringer Ingelheim.
Shares KRT-232, Myeloproliferative neoplasms (PV, ET, myelofibrosis), Small-molecule kinase inhibitors.
Shares The p53 network (guardian of the genome), p53 / RB / cell-cycle checkpoint, TP53, Acute myeloid leukaemia.
Shares Vogelstein, Lane and Levine 2000: surfing the p53 network, p53 / RB / cell-cycle checkpoint, TP53.
Shares Levine 1997: p53, the cellular gatekeeper for growth and division, Vogelstein, Lane and Levine 2000: surfing the p53 network, p53 / RB / cell-cycle checkpoint, TP53.
Shares Molecular and clinical determinants of targeted therapy treatment in biliary tract cancer, Melanoma (KEGG map), Bladder cancer (KEGG map), Glioma (KEGG map).