ArticleCancer research2019
MDM2-Recruiting PROTAC Offers Superior, Synergistic Antiproliferative Activity via Simultaneous Degradation of BRD4 and Stabilization of p53.
Article in Cancer research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 154 papers, 1 of them a synthesis that pooled it.
What it found
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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
154 citing papers in PubMed, 1 synthesis or guideline pooled it, 331 citations in OpenAlex.
- Cellular functions and molecular mechanisms of ubiquitination in osteosarcoma.Frontiers in oncology · 2022Pooled it
- Context matters in PROTAC design: navigating the trade-off between degradation and developability.Journal of enzyme inhibition and medicinal chemistry · 2026Review
- Unraveling the secrets of novel PROTACs to improve degradation efficacy.Molecular diversity · 2026Review
- Harnessing MDM2-Mediated Targeted Degradation of Transcriptional and Epigenetic Machinery to Disrupt Oncogenic Addictions in Pediatric Sarcoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Leveraging Carnitine-functionalized Lipid Nanocarrier based Targeted Delivery of A1874 PROTAC for Glioblastoma.Pharmaceutical research · 2026Article
- Eyes Toward the Clinic: Selective Inhibition and Degradation Approaches to Bromodomain-Containing Proteins.Chembiochem : a European journal of chemical biology · 2026Review
- Discovery of a KLHL41 Ligand for Muscle Specific Protein Degradation.Nature communications · 2026Article
- RING finger E3 ubiquitin ligases: novel therapeutic opportunities in melanoma.Cellular & molecular biology letters · 2026Review
- The application of drug delivery systems based on targeted protein degradation chimeras in disease treatment strategies.Journal of nanobiotechnology · 2026Review
- Mechanisms and Design Principles of Proteolysis-Targeting Chimeras and Their Emerging Applications.ACS pharmacology & translational science · 2026Review
- PROTAC internalization and target degradation require clathrin-mediated endocytosis.bioRxiv : the preprint server for biology · 2026Article
- Article
- Discovery of SKP2-Recruiting PROTACs for Target Protein Degradation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Prospects and advances of PROTAC in the treatment of hematologic malignancies.Experimental hematology & oncology · 2026Review
- The MDM2-p53 Axis in Osteosarcoma: Current Understanding of Regulatory Mechanisms and Targeted Therapeutic Strategies.Pharmaceuticals (Basel, Switzerland) · 2026Review
- PROTAC-Mediated Targeted Degradation of MDM2 Induces Tumor-Suppressive Signaling in Osteosarcoma Cells.Cells · 2026Article
- PROTAC-based protein degradation: a window of opportunity for melanoma therapy.Journal of biomedical science · 2026Review
- Proteolysis-targeting chimera (PROTAC) nanomedicines toward cancer treatment: From synthesis to therapeutic delivery.Biomaterials · 2026Review
- Targeted Protein Degradation in Lung Cancer: The Emerging Role of PROTAC Technology and E3 Ligases.Current medicinal chemistry · 2026Review
- A triple-action PROTAC for wild-type p53 cancer therapy.Cell reports. Medicine · 2025Article
94 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Although the number of proteins effectively targeted for posttranslational degradation by PROTAC has grown steadily, the number of E3 ligases successfully exploited to accomplish this has been limited to the few for which small-molecule ligands have been discovered. Although the E3 ligase MDM2 is bound by the nutlin class of small-molecule ligands, there are few nutlin-based PROTAC. Because a nutlin-based PROTAC should both knockdown its target protein and upregulate the tumor suppressor p53, we examined the ability of such a PROTAC to decrease cancer cell viability. A nutlin-based, BRD4-degrading PROTAC, A1874, was able to degrade its target protein by 98% with nanomolar potency. Given the complementary ability of A1874 to stabilize p53, we discovered that the nutlin-based PROTAC was more effective in inhibiting proliferation of many cancer cell lines with wild-type p53 than was a corresponding VHL-utilizing PROTAC with similar potency and efficacy to degrade BRD4. This is the first report of a PROTAC in which the E3 ligase ligand and targeting warhead combine to exert a synergistic antiproliferative effect. Our study highlights the untapped potential that may be unlocked by expanding the repertoire of E3 ligases that can be recruited by PROTAC. SIGNIFICANCE: These findings present the first BRD4-targeting MDM2-based PROTAC that possesses potent, distinct, and synergistic biological activities associated with both ends of this heterobifunctional molecule.
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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.