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, Subodh M Lele, Yazen Alnouti, Michael A Hollingsworth, Amarnath Natarajan

Research output: Contribution to journalArticle

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Abstract

Purpose: 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. Experimental Design: 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. Results: 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)2025-2035
Number of pages11
JournalClinical Cancer Research
Volume19
Issue number8
DOIs
StatePublished - Apr 15 2013

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Quinoxalines
Pancreatic Neoplasms
Urea
Neoplasms
Phosphotransferases
Neoplasm Metastasis
Therapeutics
Growth
Lipopolysaccharides
Research Design
Down-Regulation
Pharmacokinetics
Phosphorylation
Proteins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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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; Bryant, Vashti C.; Blowers, Elizabeth C.; Rajule, Rajkumar N.; Gautam, Nagsen; Anwar, Muhammad M.; Mohr, Ashley M.; Grandgenett, Paul M.; Bunt, Stephanie K.; Arnst, Jamie L.; Lele, Subodh M; Alnouti, Yazen; Hollingsworth, Michael A; Natarajan, Amarnath.

In: Clinical Cancer Research, Vol. 19, No. 8, 15.04.2013, p. 2025-2035.

Research output: Contribution to journalArticle

Radhakrishnan, Prakash ; Bryant, Vashti C. ; Blowers, Elizabeth C. ; Rajule, Rajkumar N. ; Gautam, Nagsen ; Anwar, Muhammad M. ; Mohr, Ashley M. ; Grandgenett, Paul M. ; Bunt, Stephanie K. ; Arnst, Jamie L. ; Lele, Subodh M ; Alnouti, Yazen ; Hollingsworth, Michael A ; Natarajan, Amarnath. / Targeting the NF-κB and mTOR pathways with a quinoxaline urea analog that inhibits IKKβ for pancreas cancer therapy. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 8. pp. 2025-2035.
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T1 - Targeting the NF-κB and mTOR pathways with a quinoxaline urea analog that inhibits IKKβ for pancreas cancer therapy

AU - Radhakrishnan, Prakash

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AU - Blowers, Elizabeth C.

AU - Rajule, Rajkumar N.

AU - Gautam, Nagsen

AU - Anwar, Muhammad M.

AU - Mohr, Ashley M.

AU - Grandgenett, Paul M.

AU - Bunt, Stephanie K.

AU - Arnst, Jamie L.

AU - Lele, Subodh M

AU - Alnouti, Yazen

AU - Hollingsworth, Michael A

AU - Natarajan, Amarnath

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N2 - Purpose: 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. Experimental Design: 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. Results: 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. Conclusion: 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.

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