2. Academic Validation
  3. Small molecule activators of TAK1 promotes its activity-dependent ubiquitination and TRAIL-mediated tumor cell death

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

  • Proc Natl Acad Sci U S A. 2023 Sep 26;120(39):e2308079120. doi: 10.1073/pnas.2308079120.
Weimin Sun 1,  Guowei Wu 1,  Xinyu Tian 1,  Chunting Qi 1,  Jingli Liu 1,  Yilun Tong 1 2,  Mengmeng Zhang 1,  Jiayang Gao 1 2,  Ze Cao 1,  Yuchao Zhang 2 3,  Zhijun Liu 4,  Xiaoxu Tian 4,  Ping Wu 4,  Chao Peng 4,  Jingwen Li 4,  Li Tan 1,  Bing Shan 1,  Jianping Liu 1,  Ying Li 1,  Junying Yuan 1
Affiliations

Affiliations

  • 1 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 National Facility for Protein Science, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201203, China.
PMID: 37733743 DOI: 10.1073/pnas.2308079120
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.

Keywords

RIPK1; TAK1; cell death.

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