Department of Stomatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL.
Int J Cancer. 2014 Apr 15;134(8):1972-80. doi: 10.1002/ijc.28507. Epub 2013 Oct 21.
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.
越来越多的证据表明，非经典 IKKs 在肿瘤发生和发展中发挥着关键作用，这使得非经典 IKKs 可能成为癌症治疗的一个良好靶点。在这里，我们证明，尽管 TBK1 在一些肿瘤细胞中没有过度表达或持续激活，但靶向 IKKi 会诱导 TBK1 的激活。因此，同时靶向这两种激酶对于有效抑制肿瘤细胞增殖是必要的。我们展示了三种基于结构刚性 2-氨基-4-(3'-氰基-4'-吡咯烷)-苯基嘧啶骨架的 TBK1/IKKi 双重抑制剂，能够强烈抑制人乳腺癌、前列腺癌和口腔癌细胞系的细胞活力。用这些 TBK1/IKKi 双重抑制剂治疗会显著损害异种移植和同种异体移植小鼠模型中的肿瘤发展。这些抑制剂的抗癌功能可能部分归因于它们抑制了 TBK1/IKKi 介导的 AKT 磷酸化和 VEGF 表达。最重要的是，这些 TBK1/IKKi 双重抑制剂具有类药性，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提供了概念验证，这可能为人类癌症的治疗带来新的策略和新的治疗方法。
