Selective TBK1/IKKi dual inhibitors with anticancer potency
| Autor: | Jijia, Li, Jingjia, Huang, Ji-Hak, Jeong, Sun-Jin, Park, Rui, Wei, Jieying, Peng, Zhiyong, Luo, Yen Ting, Chen, Yangbo, Feng, Jun-Li, Luo |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Cell Survival Mice Nude Apoptosis Breast Neoplasms Protein Serine-Threonine Kinases Article Mice Cell Line Tumor Neoplasms Animals Humans Phosphorylation RNA Small Interfering Protein Kinase Inhibitors Cell Proliferation Macrophages Tumor Suppressor Proteins Prostatic Neoplasms Cell Cycle Checkpoints Xenograft Model Antitumor Assays Deubiquitinating Enzyme CYLD I-kappa B Kinase Pyrimidines Female Mouth Neoplasms RNA Interference Proto-Oncogene Proteins c-akt |
| Zdroj: | International journal of cancer. 134(8) |
| ISSN: | 1097-0215 |
| Popis: | Increasing evidence suggests that the non-canonical IKKs play critical roles in tumor genesis and development, leading to the notion that non-canonical IKKs may be good targets for cancer therapy. Here, we demonstrate that although TBK1 is not over-expressed or constitutively activated in some tumor cells, targeting IKKi induces the activation of TBK1. Therefore, simultaneously targeting both kinases is necessary to efficiently suppress tumor cell proliferation. We show that three TBK1/IKKi dual inhibitors, which are based on a structurally rigid 2-amino-4-(3′-cyano-4′-pyrrolidine)phenyl-pyrimidine scaffold, potently inhibit cell viability in human breast, prostate, and oral cancer cell lines. Treatment with these TBK1/IKKi dual inhibitors significantly impairs tumor development in xenograft and allograft mouse models. The anti-cancer function of these inhibitors may be due partially to their suppression of TBK1/IKKi-mediated AKT phosphorylation and VEGF expression. Most importantly, these TBK1/IKKi dual inhibitors have drug-like properties including low molecular weight, low Cytochrome P450 inhibition, and high metabolic stability. Therefore, our studies provide proof of concept for further drug discovery efforts that may lead to novel strategies and new therapeutics for the treatment of human cancer. |
| Databáze: | OpenAIRE |
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