ArticleCell death & disease2018
RIPK1-dependent cell death: a novel target of the Aurora kinase inhibitor Tozasertib (VX-680).
Article in Cell death & disease, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 59 citations in OpenAlex.
- Scalable Synthesis of a Masked Thiophenol as an Air-Stable, Odorless Intermediate to the Aurora Kinase Inhibitor Tozasertib (VX-680).Organic process research & development · 2026Article
- Review on the Mechanism of and Therapies Targeting PANoptosis in Ulcerative Colitis.Biomolecules · 2026Review
- In Vitro Anticancer Activity and In Silico Target Profiling of 5-(Piperazin-1-ylsulfonyl)-1,3-oxazole-4-carbonitriles.International journal of molecular sciences · 2026Article
- Aurora kinase B as a therapeutic target in HPV-induced cervical cancer: mechanisms and future perspectives.Frontiers in oncology · 2026Review
- Targeting PANoptosis: a promising therapeutic strategy for ALI/ARDS.Apoptosis : an international journal on programmed cell death · 2025Review
- Discovery and Validation of a Novel Class of Necroptosis Inhibitors Targeting RIPK1.ACS chemical biology · 2025Article
- Aurora kinases signaling in cancer: from molecular perception to targeted therapies.Molecular cancer · 2025Review
- Article
- A deep learning framework forNational science review · 2025Article
- PANoptosis in Sepsis: A Central Role and Emerging Therapeutic Target.Journal of inflammation research · 2025Review
- Ligand-based pharmacophore modeling and machine learning for the discovery of potent aurora A kinase inhibitory leads of novel chemotypes.Molecular diversity · 2024Article
- Large-scale characterization of drug mechanism of action using proteome-wide thermal shift assays.eLife · 2024Article
- Large-scale characterization of drug mechanism of action using proteome-wide thermal shift assays.bioRxiv : the preprint server for biology · 2024Article
- Development of Biochemical and Cellular Probes to Study RIPK1 Target Engagement.ACS medicinal chemistry letters · 2024Article
- Necroptosis inhibitors: mechanisms of action and therapeutic potential.Apoptosis : an international journal on programmed cell death · 2024Review
- Text-mining-based feature selection for anticancer drug response prediction.Bioinformatics advances · 2024Article
- Mechanisms of PANoptosis and relevant small-molecule compounds for fighting diseases.Cell death & disease · 2023Review
- Immunogenic necroptosis in liver diseases: mechanisms and therapeutic potential.Journal of molecular medicine (Berlin, Germany) · 2023Review
- Role of Necroptosis in Intervertebral Disc Degeneration.International journal of molecular sciences · 2023Review
- From (Tool)Bench to Bedside: The Potential of Necroptosis Inhibitors.Journal of medicinal chemistry · 2023Review
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The Aurora kinase family (Aurora A, B and C) are crucial regulators of several mitotic events, including cytokinesis. Increased expression of these kinases is associated with tumorigenesis and several compounds targeting Aurora kinase are under evaluation in clinical trials (a.o. AT9283, AZD1152, Danusertib, MLN8054). Here, we demonstrate that the pan-Aurora kinase inhibitor Tozasertib (VX-680 and MK-0457) not only causes cytokinesis defects through Aurora kinase inhibition, but is also a potent inhibitor of necroptosis, a cell death process regulated and executed by the RIPK1, RIPK3 and MLKL signalling axis. Tozasertib's potency to inhibit RIPK1-dependent necroptosis and to block cytokinesis in cells is in the same concentration range, with an IC50 of 1.06 µM and 0.554 µM, respectively. A structure activity relationship (SAR) analysis of 67 Tozasertib analogues, modified at 4 different positions, allowed the identification of analogues that showed increased specificity for either cytokinesis inhibition or for necroptosis inhibition, reflecting more specific inhibition of Aurora kinase or RIPK1, respectively. These results also suggested that RIPK1 and Aurora kinases are functionally non-interacting targets of Tozasertib and its analogues. Indeed, more specific Aurora kinase inhibitors did not show any effect in necroptosis and Necrostatin-1s treatment did not result in cytokinesis defects, demonstrating that both cellular processes are not interrelated. Finally, Tozasertib inhibited recombinant human RIPK1, human Aurora A and human Aurora B kinase activity, but not RIPK3. The potency ranking of the newly derived Tozasertib analogues and their specificity profile, as observed in cellular assays, coincide with ADP-Glo recombinant kinase activity assays. Overall, we show that Tozasertib not only targets Aurora kinases but also RIPK1 independently, and that we could generate analogues with increased selectivity to RIPK1 or Aurora kinases, respectively.
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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.