{"entity":{"id":"mdm2","kind":"target","name":"MDM2","aka":[],"tldr":"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.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Mdm2","links":[{"label":"Liposarcoma genomics (Nat Genet 2010)","url":"https://doi.org/10.1038/ng.619"}],"tags":["gap-fill"],"related":["tp53"],"cancers":["sarcoma","glioblastoma","aml","myeloproliferative-neoplasms","gallbladder"],"sections":[],"technologies":["protac-degrader","kinase-inhibitors"],"targets":[],"drugs":["krt-232"],"companies":["boehringer-ingelheim"],"institutions":[],"pathways":["p53-cell-cycle","bladder-cancer-signalling","glioma-signalling","melanoma-signalling","prostate-cancer-signalling"],"terms":[],"trials":["nct06578624"],"people":[],"bottlenecks":[],"keyPapers":["paper-cowzer-biliary-targeted-therapy-determinants-ccr-2026","paper-barretina-nat-genet"],"journals":[],"dependsOn":[],"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."],"symbol":"MDM2","role":[],"sources":[],"specificity":"broadly-expressed","distribution":"many-types","specificityNote":"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.)","specificitySources":[{"label":"Human Protein Atlas MDM2 tissue","url":"https://www.proteinatlas.org/ENSG00000135679-MDM2/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Open Targets ENSG00000135679 associations","url":"https://platform.opentargets.org/target/ENSG00000135679/associations","note":"cancer associations at or above 0.5 (CC0)"}],"hgnc":"HGNC:6973","ensembl":"ENSG00000135679","uniprot":"Q00987","entrez":"4193","firstDescribed":1992,"firstDescribedBasis":"sequence","firstDescribedNote":"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\".","firstDescribedSource":"https://pubmed.ncbi.nlm.nih.gov/1614537/","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.","whereFound":["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%"],"targetClass":"other","prevalence":[{"cancerId":"sarcoma","pct":"90","measure":"MDM2 amplification in well/dedifferentiated liposarcoma","source":"https://doi.org/10.1038/ng.619"},{"cancerId":"gallbladder","pct":12,"measure":"Amplification","source":"https://www.cbioportal.org/study/summary?id=gbc_mskcc_2022","note":"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)."}]},"route":"/targets/mdm2/","neighbours":{"target":[{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"cancer":[{"id":"aml","kind":"cancer","name":"Acute myeloid leukaemia","route":"/cancers/aml/"},{"id":"gallbladder","kind":"cancer","name":"Gallbladder cancer","route":"/cancers/gallbladder/"},{"id":"glioblastoma","kind":"cancer","name":"Glioma & glioblastoma","route":"/cancers/glioblastoma/"},{"id":"liposarcoma","kind":"cancer","name":"Liposarcoma","route":"/cancers/liposarcoma/"},{"id":"myeloproliferative-neoplasms","kind":"cancer","name":"Myeloproliferative neoplasms (PV, ET, myelofibrosis)","route":"/cancers/myeloproliferative-neoplasms/"},{"id":"sarcoma","kind":"cancer","name":"Sarcomas (soft tissue, bone, GIST)","route":"/cancers/sarcoma/"}],"technology":[{"id":"mdm2-inhibitors","kind":"technology","name":"MDM2 inhibitors","route":"/technologies/mdm2-inhibitors/"},{"id":"protac-degrader","kind":"technology","name":"PROTACs & molecular glues (targeted protein degradation)","route":"/technologies/protac-degrader/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"drug":[{"id":"brigimadlin","kind":"drug","name":"Brigimadlin","route":"/drugs/brigimadlin/"},{"id":"krt-232","kind":"drug","name":"KRT-232","route":"/drugs/krt-232/"}],"company":[{"id":"boehringer-ingelheim","kind":"company","name":"Boehringer Ingelheim","route":"/companies/boehringer-ingelheim/"}],"pathway":[{"id":"bladder-cancer-signalling","kind":"pathway","name":"Bladder cancer (KEGG map)","route":"/pathways/bladder-cancer-signalling/"},{"id":"glioma-signalling","kind":"pathway","name":"Glioma (KEGG map)","route":"/pathways/glioma-signalling/"},{"id":"melanoma-signalling","kind":"pathway","name":"Melanoma (KEGG map)","route":"/pathways/melanoma-signalling/"},{"id":"p53-cell-cycle","kind":"pathway","name":"p53 / RB / cell-cycle checkpoint","route":"/pathways/p53-cell-cycle/"},{"id":"prostate-cancer-signalling","kind":"pathway","name":"Prostate cancer (KEGG map)","route":"/pathways/prostate-cancer-signalling/"},{"id":"p53-mdm2-axis","kind":"pathway","name":"The p53 network (guardian of the genome)","route":"/pathways/p53-mdm2-axis/"},{"id":"ubiquitin-proteasome-system","kind":"pathway","name":"Ubiquitin-proteasome system & protein homeostasis","route":"/pathways/ubiquitin-proteasome-system/"}],"trial":[{"id":"nct06578624","kind":"trial","name":"Safety and Preliminary Efficacy of SA53-OS in Patients With Locally Advanced or Metastatic Solid Tumors","route":"/trials/nct06578624/"}],"paper":[{"id":"paper-levine-p53-gatekeeper-cell-1997","kind":"paper","name":"Levine 1997: p53, the cellular gatekeeper for growth and division","route":"/key-papers/paper-levine-p53-gatekeeper-cell-1997/"},{"id":"paper-cowzer-biliary-targeted-therapy-determinants-ccr-2026","kind":"paper","name":"Molecular and clinical determinants of targeted therapy treatment in biliary tract cancer","route":"/key-papers/paper-cowzer-biliary-targeted-therapy-determinants-ccr-2026/"},{"id":"paper-barretina-nat-genet","kind":"paper","name":"Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy","route":"/key-papers/paper-barretina-nat-genet/"},{"id":"paper-vogelstein-surfing-p53-network-nature-2000","kind":"paper","name":"Vogelstein, Lane and Levine 2000: surfing the p53 network","route":"/key-papers/paper-vogelstein-surfing-p53-network-nature-2000/"}],"term":[{"id":"gene-amplification","kind":"term","name":"Gene amplification and copy-number change","route":"/terms/gene-amplification/"},{"id":"tp53-mutated","kind":"term","name":"TP53-mutated (p53-abnormal)","route":"/terms/tp53-mutated/"}]}}