ArticleProceedings of the National Academy of Sciences of the United States of America2023
Small molecule activators of TAK1 promotes its activity-dependent ubiquitination and TRAIL-mediated tumor cell death.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 10 citations in OpenAlex.
- Mechanisms, regulation and clinical relevance of necroptosis.Nature reviews. Molecular cell biology · 2026Review
- TREM1 facilitates nonresponse to anti-TNF-α monoclonal antibodies in colitis via boosting ITCH/TAK1/caspase-8 axis-mediated macrophage pyroptosis.Journal of translational medicine · 2025Article
- Exploring the Role of TRAF6-TAK1 Pathway in Podocyte Pyroptosis and Its Implications for Primary Membranous Nephropathy Therapy.Inflammation · 2025Article
- Necroptosis in cancer: insight from epigenetic, post-transcriptional and post-translational modifications.Journal of hematology & oncology · 2025Review
- Single-cell multi-dimensional data analysis decodes RNF19A-mediated drug resistance in rheumatoid arthritis fibroblast-like synoviocytes: mechanisms and biological insights.Cellular and molecular life sciences : CMLS · 2025Article
- Cooperation of TRADD- and RIPK1-dependent cell death pathways in maintaining intestinal homeostasis.Nature communications · 2025Article
- Bioinformatics meets machine learning: identifying circulating biomarkers for vitiligo across blood and tissues.Frontiers in immunology · 2025Article
- A guide to cell death pathways.Nature reviews. Molecular cell biology · 2024Review
Corrections and comments
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Authors and funding
20 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
TAK1 is a key modulator of both NF-κB signaling and RIPK1. In TNF signaling pathway, activation of TAK1 directly mediates the phosphorylation of IKK complex and RIPK1. In a search for small molecule activators of RIPK1-mediated necroptosis, we found R406/R788, two small molecule analogs that could promote sustained activation of TAK1. Treatment with R406 sensitized cells to TNF-mediated necroptosis and RIPK1-dependent apoptosis by promoting sustained RIPK1 activation. Using click chemistry and multiple biochemical binding assays, we showed that treatment with R406 promotes the activation of TAK1 by directly binding to TAK1, independent of its original target Syk kinase. Treatment with R406 promoted the ubiquitination of TAK1 and the interaction of activated TAK1 with ubiquitinated RIPK1. Finally, we showed that R406/R788 could promote the cancer-killing activities of TRAIL in vitro and in mouse models. Our studies demonstrate the possibility of developing small molecule TAK1 activators to potentiate the effect of TRAIL as anticancer therapies.
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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.