Selective TBK1/IKKi dual inhibitors with anticancer potency

Abstract

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. What's new? The IKK kinases regulate transcription factors known to play a role in cancer. Recent evidence suggests that two lesser-known IKKs, IKKi and TBK1, are important in the tumorigenesis and growth of some tumors. In this study, the authors found that targeting both of these kinases simultaneously is necessary in order to suppress proliferation in these tumors. They also demonstrate that TBK1/IKKi dual inhibitors have potent anti-tumor effects in mice. These inhibitors possess properties crucial for viable drug candidates, and may thus lead to novel treatment strategies and more efficient cancer therapeutics. © 2013 UICC.