Selective TBK1/IKKi dual inhibitors with anticancer potency

Abstract

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.

Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

“…These observations highlight a critical role of autophagy and/or inflammation in disease predisposition. It is also noteworthy that many drugs have been developed that act on TBK1-mediated pathways owing to their role in tumor cell survival (47) and can therefore be used to investigate the effects of drug-dependent loss of function of the kinase.…”

Evaluating TBK1 as a Therapeutic Target in Cancers with Activated IRF3

“…Collectively, these knockdown studies argue that the role of TBK1 in cell proliferation and growth mechanisms still remain to be elucidated. Identifying these determinants and codependencies, especially in the context of RAS mutations, could still have significant implications for targeted therapy of KRAS-mutant cancers (40).…”

“…Therefore, TBK1 inhibition alone is not sufficient to drive a robust growth inhibition phenotype in these cell lines. It is possible that by combining inhibitors of other KRAS-activated pathways would be a more effective treatment paradigm (40).…”

TBK1 inhibitors: a review of patent literature (2011 – 2014)

“…A structurally rigid 2-amino-4-(30-cyano-40-pyrrolidine)phenyl-pyrimidine scaffold was patented by researchers at the Scripps Research Institute of United States as a potent TBK1 inhibitor [39]. As compound SR8185 was reported as a JNK inhibitor candidate, this group modified the structure of SR8185 and explored structure--activity relationship studies, and successfully generated compounds 34 and 35 with excellent inhibition and specificity for TBK1 (IC 50 values were both lower than 1 nM) ( Figure 8).…”