ArticleJournal of medicinal chemistry2025
Second-Generation AURKA-Targeting PROTACs: Structural Optimization toward in Vivo Degradation in Neuroblastoma.
Article in Journal of medicinal chemistry, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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.
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Who cites it
6 citing papers in PubMed.
- Evolving CRBN ligands enhance the drug-like properties of protein degraders.Journal of enzyme inhibition and medicinal chemistry · 2026Review
- Expanding Synthetic Lethality in DNA Damage Response-Defective Cancers Through Stress Phenotype-Guided Kinase Targeting.International journal of molecular sciences · 2026Review
- Targeting MYCN Degradation by HLB-0532259 Induces Senescence in Retinoblastoma.Investigative ophthalmology & visual science · 2026Article
- Targeting the MYCN interaction network in neuroblastoma.Bioscience reports · 2026Review
- Review
- Unveiling the molecular landscape: Long non-coding RNAs in neuroblastoma (Review).Oncology reports · 2026Review
Corrections and comments
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Authors and funding
17 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Aurora kinase A (AURKA) is an established oncogenic factor and therapeutic target in neuroblastoma due to its roles in mitosis and stability of the MYCN protein. We previously identified SK2188 as a highly potent, selective, and fast-acting AURKA degrader capable of inducing MYCN destabilization. However, SK2188 showed low systemic exposure and rapid clearance in mice, necessitating further chemical optimization. Here, we describe our structure-activity optimization efforts involving linker rigidification and incorporation of alternative cereblon- and AURKA-recruiting ligands, leading to two optimized PROTACs, SK4454 and SK5527. Both compounds retained rapid and selective AURKA degradation with improved pharmacokinetic properties. Importantly, single intravenous administration of either degrader efficiently reduced AURKA levels in vivo in a neuroblastoma xenograft mouse model. Moreover, MDR1-mediated PROTAC efflux was identified as a key intrinsic mechanism limiting in vitro potency. These results establish SK4454 and SK5527 as advanced AURKA degraders with improved pharmacokinetic properties, warranting further preclinical evaluation.
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Registered trials
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