Purpose The presence of TNFα in ~ 50% of surgically resected tumors suggests that the canonical NF-κB and the mTOR pathways are activated. 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 TNFα mediated NF-κB transcription in cells with low-μM potency. 13-197 inhibited the phosphorylation of IκBα, S6K and eIF4EBP, induced G1 arrest and down regulated the expression of antiapoptotic proteins in pancreatic cancer cells. Prolonged administration of 13-197 did not induce granulocytosis and protected mice from 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.

Adenosine 5′-monophosphate activated protein kinase (AMPK) is a master sensor of cellular energy status that plays a key role in the regulation of whole-body energy homeostasis. AMPK is a serine/threonine kinase that is activated by upstream kinases LKB1, CaMKKβ and Tak1 among others. AMPK exists as αβγ trimeric complexes that are allosterically regulated by AMP, ADP and ATP. Dysregulation of AMPK has been implicated in a number of metabolic diseases including type 2 diabetes mellitus and obesity. Recent studies have associated roles of AMPK with the development of cancer and neurological conditions making it a potential therapeutic target to treat human diseases. This perspective focuses on the structure and function of AMPK, its role in human diseases and its direct substrates and provides a brief synopsis of key AMPK modulators and their relevance in human diseases.

Design, synthesis, and evaluation of α-methylene-γ-butyrolactone analogues and their evaluation as anticancer agents is described. SAR identified a spirocyclic analogue 19 that inhibited TNFα-induced NF-κB activity, cancer cell growth and tumor growth in an ovarian cancer model. A second iteration of synthesis and screening identified 29 which inhibited cancer cell growth with low-μM potency. Our data suggest that an isatin-derived spirocyclic α-methylene-γ-butyrolactone is a suitable core for optimization to identify novel anticancer agents.

<p>PDF file - 53K, Table S1: Pancreatic cancer cell growth inhibition by 13-197; Table S2: % Neutrophils upon prolonged treatment with 13-197; Table S3: Metastases in mice treated with 13-197; Table S4: Immunohistochemical analysis of tumor samples; Table S5: Inflammation and Necrosis in tumor tissues</p>

<p>PDF file - 76K, Dose and time dependent effect of 13-197 on Capan2 cell growth</p>