# MDM2

Source: https://onco.cc/targets/mdm2/  
OnCo record `mdm2` (Target). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Target
- Last checked: 2026-09-08
- Tags: gap-fill
- Symbol: MDM2
- Class: other
- Biology: 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.
- Where found: Well-differentiated / dedifferentiated liposarcoma (>90% amplification); Intimal sarcoma, low-grade central osteosarcoma; Glioblastoma (~5-10%); Breast, lung, bladder cancer (subsets); TP53-wild-type AML and myelofibrosis (pharmacologic target); Gallbladder cancer: amplification about 12%

## Notes

- Gallbladder cancer: MDM2 amplification in about 12% of MSK samples (cBioPortal gbc_mskcc_2022 and gbc_msk_2018) and 6.5% of biliary tract cancers overall (Cowzer 2026), an emerging target in TP53 wild-type tumours.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Mdm2
- Liposarcoma genomics (Nat Genet 2010): https://doi.org/10.1038/ng.619

## Connected records

- targets: [TP53](https://onco.cc/targets/tp53/)
- cancers: [Acute myeloid leukaemia](https://onco.cc/cancers/aml/), [Gallbladder cancer](https://onco.cc/cancers/gallbladder/), [Glioma & glioblastoma](https://onco.cc/cancers/glioblastoma/), [Liposarcoma](https://onco.cc/cancers/liposarcoma/), [Myeloproliferative neoplasms (PV, ET, myelofibrosis)](https://onco.cc/cancers/myeloproliferative-neoplasms/), [Sarcomas (soft tissue, bone, GIST)](https://onco.cc/cancers/sarcoma/)
- technologies: [MDM2 inhibitors](https://onco.cc/technologies/mdm2-inhibitors/), [PROTACs & molecular glues (targeted protein degradation)](https://onco.cc/technologies/protac-degrader/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- drugs: [Brigimadlin](https://onco.cc/drugs/brigimadlin/), [KRT-232](https://onco.cc/drugs/krt-232/)
- companies: [Boehringer Ingelheim](https://onco.cc/companies/boehringer-ingelheim/)
- pathways: [Bladder cancer (KEGG map)](https://onco.cc/pathways/bladder-cancer-signalling/), [Glioma (KEGG map)](https://onco.cc/pathways/glioma-signalling/), [Melanoma (KEGG map)](https://onco.cc/pathways/melanoma-signalling/), [p53 / RB / cell-cycle checkpoint](https://onco.cc/pathways/p53-cell-cycle/), [Prostate cancer (KEGG map)](https://onco.cc/pathways/prostate-cancer-signalling/), [The p53 network (guardian of the genome)](https://onco.cc/pathways/p53-mdm2-axis/), [Ubiquitin-proteasome system & protein homeostasis](https://onco.cc/pathways/ubiquitin-proteasome-system/)
- trials: [Safety and Preliminary Efficacy of SA53-OS in Patients With Locally Advanced or Metastatic Solid Tumors](https://onco.cc/trials/nct06578624/)
- key papers: [Levine 1997: p53, the cellular gatekeeper for growth and division](https://onco.cc/key-papers/paper-levine-p53-gatekeeper-cell-1997/), [Molecular and clinical determinants of targeted therapy treatment in biliary tract cancer](https://onco.cc/key-papers/paper-cowzer-biliary-targeted-therapy-determinants-ccr-2026/), [Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy](https://onco.cc/key-papers/paper-barretina-nat-genet/), [Vogelstein, Lane and Levine 2000: surfing the p53 network](https://onco.cc/key-papers/paper-vogelstein-surfing-p53-network-nature-2000/)
- terms: [Gene amplification and copy-number change](https://onco.cc/terms/gene-amplification/), [TP53-mutated (p53-abnormal)](https://onco.cc/terms/tp53-mutated/)

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