Data from Targeting the NF-κB and mTOR Pathways with a Quinoxaline Urea Analog That Inhibits IKKβ for Pancreas Cancer Therapy

Abstract

<div>Abstract<p><b>Purpose:</b> The presence of TNF-α in approximately 50% of surgically resected tumors suggests that the canonical NF-κB and the mTOR pathways are activated. Inhibitor of IκB kinase β (IKKβ) acts as the signaling node that regulates transcription via the p-IκBα/NF-κB axis and regulates translation via the mTOR/p-S6K/p-eIF4EBP axis. A kinome screen identified a quinoxaline urea analog 13-197 as an IKKβ inhibitor. We hypothesized that targeting the NF-κB and mTOR pathways with 13-197 will be effective in malignancies driven by these pathways.</p><p><b>Experimental Design:</b> Retrospective clinical and preclinical studies in pancreas cancers have implicated NF-κB. We examined the effects of 13-197 on the downstream targets of the NF-κB and mTOR pathways in pancreatic cancer cells, pharmacokinetics, toxicity and tumor growth, and metastases <i>in vivo</i>.</p><p><b>Results:</b> 13-197 inhibited the kinase activity of IKKβ <i>in vitro</i> and TNF-α–mediated NF-κB transcription in cells with low-μmol/L potency. 13-197 inhibited the phosphorylation of IκBα, S6K, and eIF4EBP, induced G<sub>1</sub> arrest, and downregulated the expression of antiapoptotic proteins in pancreatic cancer cells. Prolonged administration of 13-197 did not induce granulocytosis and protected mice from lipopolysaccharide (LPS)-induced death. Results also show that 13-197 is orally available with extensive distribution to peripheral tissues and inhibited tumor growth and metastasis in an orthotopic pancreatic cancer model without any detectable toxicity.</p><p><b>Conclusion:</b> These results suggest that 13-197 targets IKKβ and thereby inhibits mTOR and NF-κB pathways. Oral availability along with <i>in vivo</i> efficacy without obvious toxicities makes this quinoxaline urea chemotype a viable cancer therapeutic. <i>Clin Cancer Res; 19(8); 2025–35. ©2013 AACR</i>.</p></div>