ArticleLeukemia2023
An MDM2 degrader for treatment of acute leukemias.
Article in Leukemia, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 17 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
17 citing papers in PubMed, 29 citations in OpenAlex.
- Fundamentals and emerging frontiers in p53-targeted drug development.Biochemistry and biophysics reports · 2026Review
- TRIM22-mediated ubiquitin-dependent degradation of FLT3-ITD overcomes TKI resistance in acute myeloid leukemia.Life medicine · 2026Article
- MDM2 inhibitors in myeloid cancers: from basic biology to clinical use in myeloproliferative neoplasms.Leukemia · 2026Review
- Unraveling the role ofHemaSphere · 2026Review
- PROTAC-based protein degradation: a window of opportunity for melanoma therapy.Journal of biomedical science · 2026Review
- Characterization of a dual degrader of MDM2 and GSPT1.European journal of medicinal chemistry · 2025Article
- High Mobility Group A1 Chromatin Keys: Unlocking the Genome During MPN Progression.International journal of molecular sciences · 2025Review
- Harnessing p53 for targeted cancer therapy: new advances and future directions.Transcription · 2025Review
- Dual inhibitor of MDM2 and NFAT1 for experimental therapy of breast cancer:Frontiers in pharmacology · 2025Article
- Licochalcone A decreases cancer cell proliferation and enhances ferroptosis in acute myeloid leukemia through suppressing the IGF2BP3/MDM2 cascade.Annals of hematology · 2024Article
- PROteolysis-Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives.MedComm · 2024Review
- Review
- MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future.Pharmacological reviews · 2024Review
- Design-rules for stapled peptides with in vivo activity and their application to Mdm2/X antagonists.Nature communications · 2024Article
- Targeting reversible post-translational modifications with PROTACs: a focus on enzymes modifying protein lysine and arginine residues.Journal of enzyme inhibition and medicinal chemistry · 2023Review
- Advancements in MDM2 inhibition: Clinical and pre-clinical investigations of combination therapeutic regimens.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2023Review
- Review
Corrections and comments
- Erratum issued
Authors and funding
18 authors at 3 institutions in 2 countries.
Funding
Abstract
In acute myeloid leukemia (AML), p53 tumor suppressor activity can be reduced due to enhanced expression of MDM2 which promotes the degradation of p53. In TP53 wild-type malignancies, therapy with small molecule antagonists of MDM2 results in antileukemic activity. Current treatment strategies, however, have been limited by poor tolerability and incomplete clinical activity. We have developed a proteolysis-targeting chimera (PROTAC) MS3227 that targets MDM2 by recruiting the E3 ligase Von Hippel-Lindau, resulting in proteasome-dependent degradation of MDM2. In WT TP53 leukemia cell lines, MS3227 led to activation of p53 targets p21, PUMA, and MDM2 and resulted in cell-cycle arrest, apoptosis, and decreased viability. The catalytic PROTAC MS3227 led to more potent activation when compared to a stoichiometric inhibitor, in part by dampening the negative feedback mechanism in the p53 - MDM2 circuit. The effectiveness of MS3227 was also observed in primary patient specimens with selectivity towards leukemic blasts. The addition of MS3227 enhanced the activity of other anti-leukemic agents including azacytidine, cytarabine, and venetoclax. In particular, MS3227 treatment was shown to downregulate MCL-1, a known mediator of resistance to venetoclax. A PROTAC-based approach may provide a means of improving MDM2 inhibition to gain greater therapeutic potential in AML.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.