nutlin-3a
Overview
Nutlin-3a is a small-molecule cis-imidazoline compound that blocks the MDM2–p53 protein-protein interaction, preventing MDM2-mediated ubiquitination and proteasomal degradation of p53. By stabilizing wild-type p53 protein, it activates p53 transcriptional programs (cell-cycle arrest, apoptosis) in tumors that retain WT TP53. Approval status: investigational/preclinical tool compound; clinical-stage successors (e.g., AMG 232, idasanutlin) have entered trials.
Evidence in the corpus
- MDM2 is focally amplified on chromosome 12q in ~90% of DDLS (dedifferentiated liposarcoma). An shRNA screen of 385 12q-resident genes in DDLS cell lines identified MDM2 as an anti-proliferative dependency (sustained knockdown >1 week required). YEATS4 (GAS41) is co-amplified with MDM2 on 12q and proposed to cooperatively repress the p53 network; nutlin-3a is explicitly cited as a rationale compound for clinical evaluation targeting the MDM2–p53 axis in DDLS PMID:20601955.
- Included in the CCLE pharmacogenomic screen across 947 cancer cell lines; sensitivity correlated with genomic features via elastic-net regression PMID:22460905
Resistance mechanisms
- Efficacy is contingent on wild-type TP53 status; tumors with TP53 mutation (17% of PLLS in this cohort) are expected to be insensitive PMID:20601955.
Cancer types (linked)
Sources
- PMID:20601955 — Barretina et al. 2010, Nature Genetics; MDM2 + YEATS4 co-amplification on 12q in DDLS; nutlin-3a proposed as MDM2-antagonist therapeutic rationale.
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