Small molecule activators of TAK1 promotes its activity-dependent ubiquitination and TRAIL-mediated tumor cell death

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 p...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 120; no. 39; p. e2308079120
Main Authors Sun, Weimin, Wu, Guowei, Tian, Xinyu, Qi, Chunting, Liu, Jingli, Tong, Yilun, Zhang, Mengmeng, Gao, Jiayang, Cao, Ze, Zhang, Yuchao, Liu, Zhijun, Tian, Xiaoxu, Wu, Ping, Peng, Chao, Li, Jingwen, Tan, Li, Shan, Bing, Liu, Jianping, Li, Ying, Yuan, Junying
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 26.09.2023
Subjects
Animal models
Animals
Anticancer properties
Apoptosis
Binding
Biological Sciences
Cell Death
Chemical synthesis
Cytosol
Kinases
Mice
Necroptosis
Neoplasms - drug therapy
Neoplasms - genetics
NF-κB protein
Phosphorylation
Signal transduction
Syk protein
TAK1 protein
Tumor necrosis factor
Ubiquitination
TAK1
cell death
RIPK1
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Summary: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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Contributed by Junying Yuan; received May 15, 2023; accepted August 4, 2023; reviewed by Jun Ninomiya-Tsuji and Eileen White
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2308079120