Logo image
Back
Targeting the NF-κB and mTOR pathways with a quinoxaline urea analog that inhibits IKKβ for pancreas cancer therapy
Journal article   Open access   Peer reviewed

Targeting the NF-κB and mTOR pathways with a quinoxaline urea analog that inhibits IKKβ for pancreas cancer therapy

Prakash Radhakrishnan, Vashti C Bryant, Elizabeth C Blowers, Rajkumar N Rajule, Nagsen Gautam, Muhammad M Anwar, Ashley M Mohr, Paul M Grandgenett, Stephanie K Bunt, Jamie L Arnst, …
Clinical cancer research, Vol.19(8), pp.2025-2035
04/15/2013
DOI: 10.1158/1078-0432.CCR-12-2909
PMCID: PMC3630250
PMID: 23444213
url
https://doi.org/10.1158/1078-0432.CCR-12-2909View
Published (Version of record) Open Access

Abstract

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. 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 in vivo. 13-197 inhibited the kinase activity of IKKβ in vitro 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 G1 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. These results suggest that 13-197 targets IKKβ and thereby inhibits mTOR and NF-κB pathways. Oral availability along with in vivo efficacy without obvious toxicities makes this quinoxaline urea chemotype a viable cancer therapeutic.
 Animals Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Apoptosis Regulatory Proteins - metabolism Area Under Curve Blotting, Western Cell Line, Tumor Cell Movement - drug effects Cell Proliferation - drug effects G1 Phase Cell Cycle Checkpoints - drug effects Humans I-kappa B Kinase - antagonists & inhibitors I-kappa B Kinase - metabolism Immunohistochemistry Mice Mice, Inbred BALB C Mice, Nude NF-kappa B - metabolism Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Phenylurea Compounds - chemistry Phenylurea Compounds - pharmacokinetics Phenylurea Compounds - pharmacology Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - pharmacology Quinoxalines - chemistry Quinoxalines - pharmacokinetics Quinoxalines - pharmacology Signal Transduction - drug effects TOR Serine-Threonine Kinases - metabolism Tumor Burden - drug effects Xenograft Model Antitumor Assays

Details

Metrics

17 Record Views
32 Times Cited - Web of Science
Logo image