ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2022
A Temporal PROTAC Cocktail-Mediated Sequential Degradation of AURKA Abrogates Acute Myeloid Leukemia Stem Cells.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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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.
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Who cites it
23 citing papers in PubMed, 44 citations in OpenAlex.
- AURORA A interacts with DICER and SETD2 to promote S-phase progression.EMBO reports · 2026Article
- KMT2D loss drives adeno-to-squamous transition and sensitizes TKI-resistant lung cancer to AURKA inhibition.Cell death and differentiation · 2026Article
- Revolutionizing protein degradation: Harnessing nanoparticles for PROTAC delivery.Materials today. Bio · 2026Review
- Prospects and advances of PROTAC in the treatment of hematologic malignancies.Experimental hematology & oncology · 2026Review
- Unhooking the Hook: Optimization of the Aurora A Targeting PROTACJournal of medicinal chemistry · 2026Article
- Second-Generation AURKA-Targeting PROTACs: Structural Optimization toward in Vivo Degradation in Neuroblastoma.Journal of medicinal chemistry · 2025Article
- Discovery of the first-in-class Aurora B kinase selective degrader.European journal of medicinal chemistry · 2025Article
- Exploiting targeted degradation of cyclins and cyclin-dependent kinases for cancer therapeutics: a review.Journal of Zhejiang University. Science. B · 2025Review
- Razing the scaffolding: the elimination of non-catalytic functions of kinases through targeted protein degradation.RSC medicinal chemistry · 2025Review
- Aurora kinases signaling in cancer: from molecular perception to targeted therapies.Molecular cancer · 2025Review
- Cellular parameters shaping pathways of targeted protein degradation.Communications biology · 2025Review
- Transcriptomic profiling reveals mechanism, therapeutic potential, and prognostic value of cancer stemness characteristic in nasopharyngeal carcinoma.Functional & integrative genomics · 2025Article
- Development of Dual Aurora-A and Aurora-B Degrading PROTACs forChemMedChem · 2025Article
- CD69 predicts prognosis through immune cell infiltration and decitabine treatment response in acute myeloid leukemia.Translational cancer research · 2025Article
- Molecular regulation and therapeutic targeting ofFrontiers in cell and developmental biology · 2025Review
- Article
- Research progress on the relationship between AURKA and tumorigenesis: the neglected nuclear function of AURKA.Annals of medicine · 2024Review
- Review
- Article
- Aurora kinase A promotes hepatic stellate cell activation and liver fibrosis through the Wnt/β-catenin pathway.Frontiers in oncology · 2024Article
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Authors and funding
21 authors at 3 institutions in 1 country.
Funding
Abstract
AURKA is a potential kinase target in various malignancies. The kinase-independent oncogenic functions partially disclose the inadequate efficacy of the kinase inhibitor in a Phase III clinical trial. Simultaneously targeting the catalytic and noncatalytic functions of AURKA may be a feasible approach. Here, a set of AURKA proteolysis targeting chimeras (PROTACs) are developed. The CRBN-based dAurA383 preferentially degrades the highly abundant mitotic AURKA, while cIAP-based dAurA450 degrades the lowly abundant interphase AURKA in acute myeloid leukemia (AML) cells. The proteomic and transcriptomic analyses indicate that dAurA383 triggers the "mitotic cell cycle" and "stem cell" processes, while dAurA450 inhibits the "MYC/E2F targets" and "stem cell" processes. dAurA383 and dAurA450 are combined as a PROTAC cocktail. The cocktail effectively degrades AURKA, relieves the hook effect, and synergistically inhibits AML stem cells. Furthermore, the PROTAC cocktail induces AML regression in a xenograft mouse model and primary patient blasts. These findings establish the PROTAC cocktail as a promising spatial-temporal drug administration strategy to sequentially eliminate the multifaceted functions of oncoproteins, relieve the hook effect, and prevent cancer stem cell-mediated drug resistance.
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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.