Selective TBK1/IKKi dual inhibitors with anticancer potency.
Selective TBK1/IKKi dual inhibitors with anticancer potency.
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具有抗癌功效的选择性 TBK1/IKKi 双重抑制剂
DOI：
10.1002/ijc.28507
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发表时间：
2014-04-15
影响因子：
6.4
通讯作者：
Luo, Jun-Li
中科院分区：
文献类型：
--
作者：
Li, Jijia;Huang, Jingjia;Jeong, Ji-Hak;Park, Sun-Jin;Wei, Rui;Peng, Jieying;Luo, Zhiyong;Chen, Yen Ting;Feng, Yangbo;Luo, Jun-Li
越来越多的证据表明，非经典IKK在肿瘤的发生和发展中起着关键作用，这使得人们认为非经典IKK可能是肿瘤治疗的良好靶点。在这里，我们证明，虽然TBK 1在某些肿瘤细胞中没有过表达或组成性激活，但靶向IKKi诱导TBK 1的激活。因此，同时靶向两种激酶对于有效抑制肿瘤细胞增殖是必要的。我们发现，三种基于结构刚性的2-氨基-4-（3′-氰基-4 ′-吡咯烷）苯基-嘧啶支架的TBK 1/IKKi双重抑制剂有效抑制人乳腺癌、前列腺癌和口腔癌细胞系中的细胞活力。用这些TBK 1/IKKi双重抑制剂治疗显著损害异种移植物和同种异体移植物小鼠模型中的肿瘤发展。这些抑制剂的抗癌功能可能部分是由于它们抑制TBK 1/IKKi介导的AKT磷酸化和VEGF表达。最重要的是，这些TBK 1/IKKi双重抑制剂具有药物样性质，包括低分子量，低细胞色素P450抑制和高代谢稳定性。因此，我们的研究为进一步的药物发现工作提供了概念证明，这可能导致治疗人类癌症的新策略和新疗法。
Increasing evidence suggests that the noncanonical IKKs play critical roles in tumor genesis and development, leading to the notion that noncanonical IKKs may be good targets for cancer therapy. Here, we demonstrate that although TBK1 is not overexpressed 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 anticancer function of these inhibitors may be partially due 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.
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影响因子：
11.4
作者：
Bonnard, M;Mirtsos, C;Yeh, WC
通讯作者：
Yeh, WC
影响因子：
5.3
作者：
Fujita, F;Taniguchi, Y;Nakanishi, M
通讯作者：
Nakanishi, M
影响因子：
56.9
作者：
tenOever, Benjamin R.;ng, Sze-Li Ng;Maniatis, Tom
通讯作者：
Maniatis, Tom
影响因子：
64.5
作者：
Chien, Yuchen;Kim, Sungchan;White, Michael A.
通讯作者：
White, Michael A.
影响因子：
82.9
作者：
Chen, JH;Somanath, PR;Byzova, TV
通讯作者：
Byzova, TV