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.
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.
- Target · the protein and the cell it sits on
- Drug · antibody, small molecule, cell or radioligand
- Effect · signal, damage or kill
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.
- 1 · What it is
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.
- 2 · What goes wrong in cancer
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.
- 3 · How drugs use it
No product in this corpus aims at MDM2 yet. Drugs bind the molecule precisely: to switch it off, flag the cell for the immune system, or deliver a payload.
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.
- 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)
How common it is, by cancer
Latest papers
topQuery 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.