title: Targeting the NF-κB and mTOR pathways with a quinoxaline urea analog that inhibits IKKβ for pancreas cancer therapy.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors: Eppley Institute for Cancer Research and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
authors: Prakash
authors: P
authors: Radhakrishnan
authors: Vashti C
authors: VC
authors: Bryant
authors: Elizabeth C
authors: EC
authors: Blowers
authors: Rajkumar N
authors: RN
authors: Rajule
authors: Nagsen
authors: N
authors: Gautam
authors: Muhammad M
authors: MM
authors: Anwar
authors: Ashley M
authors: AM
authors: Mohr
authors: Paul M
authors: PM
authors: Grandgenett
authors: Stephanie K
authors: SK
authors: Bunt
authors: Jamie L
authors: JL
authors: Arnst
authors: Subodh M
authors: SM
authors: Lele
authors: Yazen
authors: Y
authors: Alnouti
authors: Michael A
authors: MA
authors: Hollingsworth
authors: Amarnath
authors: A
authors: Natarajan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D019540:Area Under Curve; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010671:Phenylurea Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011810:Quinoxalines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C584232:13-197 compound; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D016328:NF-kappa B; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011810:Quinoxalines; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D051550:I-kappa B Kinase