ArticleBritish journal of pharmacology2019
Identification of the Raf kinase inhibitor TAK-632 and its analogues as potent inhibitors of necroptosis by targeting RIPK1 and RIPK3.
Article in British journal of pharmacology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 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
22 citing papers in PubMed, 55 citations in OpenAlex.
- Discovery of novel RIPK3 inhibitors by virtual screening and bioactivity evaluation.Molecular diversity · 2026Article
- Small molecules targeting regulated cell death for chronic kidney disease therapy.Journal of pharmaceutical analysis · 2026Review
- Review
- Focus on necroptosis: its role in the pathogenesis and therapeutic potential of osteoarthritis.Frontiers in immunology · 2026Review
- Targeting PANoptosis: a promising therapeutic strategy for ALI/ARDS.Apoptosis : an international journal on programmed cell death · 2025Review
- Structure-based design of potent and selective inhibitors targeting RIPK3 for eliminating on-target toxicity in vitro.Nature communications · 2025Article
- Structure-Activity Relationship Study of (ACS pharmacology & translational science · 2024Article
- Construction of luciferase-expressing Neospora caninum and drug screening.Parasites & vectors · 2024Article
- Necroptosis inhibitors: mechanisms of action and therapeutic potential.Apoptosis : an international journal on programmed cell death · 2024Review
- Protective Effect of a Novel RIPK1 Inhibitor, Compound 4-155, in Systemic Inflammatory Response Syndrome and Sepsis.Inflammation · 2023Article
- Vemurafenib inhibits necroptosis in normal and pathological conditions as a RIPK1 antagonist.Cell death & disease · 2023Article
- Repurposing of the FGFR inhibitor AZD4547 as a potent inhibitor of necroptosis by selectively targeting RIPK1.Acta pharmacologica Sinica · 2023Article
- From (Tool)Bench to Bedside: The Potential of Necroptosis Inhibitors.Journal of medicinal chemistry · 2023Review
- Curcumin alleviates experimental colitis in mice by suppressing necroptosis of intestinal epithelial cells.Frontiers in pharmacology · 2023Article
- Necroptosis and Alzheimer's Disease: Pathogenic Mechanisms and Therapeutic Opportunities.Journal of Alzheimer's disease : JAD · 2023Review
- Necroptosis: A Pathogenic Negotiator in Human Diseases.International journal of molecular sciences · 2022Review
- Necroptosis in CNS diseases: Focus on astrocytes.Frontiers in aging neuroscience · 2022Review
- Review
- Ligand-based substituent-anchoring design of selective receptor-interacting protein kinase 1 necroptosis inhibitors for ulcerative colitis therapy.Acta pharmaceutica Sinica. B · 2021Article
- Knocking 'em Dead: Pore-Forming Proteins in Immune Defense.Annual review of immunology · 2020Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
Abstract
background and purposeNecroptosis is a form of programmed, caspase-independent, cell death, mediated by receptor-interacting protein kinases, RIPK1 and RIPK3, and the mixed lineage kinase domain-like (MLKL). Necroptosis contributes to the pathophysiology of various inflammatory, infectious, and degenerative diseases. Thus, identification of low MW inhibitors for necroptosis has broad therapeutic relevance. Here, we identified that the pan-Raf inhibitor TAK-632 was also an inhibitor of necroptosis. We have further generated a more selective, highly potent analogue of TAK-632 by targeting RIPK1 and RIPK3. EXPERIMENTAL APPROACH: Cell viability was measured by MTT, propidium staining, or CellTiter-Glo luminescent assays. Effects of TAK-632 on necroptosis signalling pathways were investigated by western blotting, immunoprecipitation, and in vitro kinase assays. Downstream targets of TAK-632 were identified by a drug affinity responsive target stability assay and a pull-down assay with biotinylated TAK-632. A mouse model of TNF-α-induced systemic inflammatory response syndrome (SIRS) was further used to explore the role of TAK-632 in protecting against necroptosis-associated inflammation in vivo. KEY
resultsTAK-632 protected against necroptosis in human and mouse cells but did not protect cells from apoptosis. TAK-632 directly bound with RIPK1 and RIPK3 to inhibit kinase activities of both enzymes. In vivo, TAK-632 alleviated TNF-induced SIRS. Furthermore, we performed a structure-activity relationship analysis of TAK-632 analogues and generated SZM594, a highly potent inhibitor of RIPK1/3. CONCLUSIONS AND IMPLICATIONS: TAK-632 is an inhibitor of necroptosis and represents a new lead compound in the development of highly potent inhibitors of RIPK1 and RIPK3.
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.