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Targeting the NF-?B and mTOR pathways with a quinoxaline urea analog that inhibits IKK? for pancreas cancer therapy.

ABSTRACT: The presence of TNF-? in approximately 50% of surgically resected tumors suggests that the canonical NF-?B and the mTOR pathways are activated. Inhibitor of I?B kinase ? (IKK?) acts as the signaling node that regulates transcription via the p-I?B?/NF-?B axis and regulates translation via the mTOR/p-S6K/p-eIF4EBP axis. A kinome screen identified a quinoxaline urea analog 13-197 as an IKK? inhibitor. We hypothesized that targeting the NF-?B 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-?B. We examined the effects of 13-197 on the downstream targets of the NF-?B and mTOR pathways in pancreatic cancer cells, pharmacokinetics, toxicity and tumor growth, and metastases in vivo.13-197 inhibited the kinase activity of IKK? in vitro and TNF-?-mediated NF-?B transcription in cells with low-?mol/L potency. 13-197 inhibited the phosphorylation of I?B?, 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 IKK? and thereby inhibits mTOR and NF-?B pathways. Oral availability along with in vivo efficacy without obvious toxicities makes this quinoxaline urea chemotype a viable cancer therapeutic.

SUBMITTER: Radhakrishnan P

PROVIDER: S-EPMC3630250 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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

Radhakrishnan Prakash P Bryant Vashti C VC Blowers Elizabeth C EC Rajule Rajkumar N RN Gautam Nagsen N Anwar Muhammad M MM Mohr Ashley M AM Grandgenett Paul M PM Bunt Stephanie K SK Arnst Jamie L JL Lele Subodh M SM Alnouti Yazen Y Hollingsworth Michael A MA Natarajan Amarnath A

Clinical cancer research : an official journal of the American Association for Cancer Research 20130226 8

<h4>Purpose</h4>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 eff ...[more]

PMID: 23444213

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Dataset Information

Targeting the NF-?B and mTOR pathways with a quinoxaline urea analog that inhibits IKK? for pancreas cancer therapy.

Publications

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

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