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

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 ß (IKKß) 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 IKKß 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 IKKß 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 IKKß 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.

Perturbing pro-survival proteins using quinoxaline derivatives: a structure-activity relationship study.

In HeLa cells the combinatorial knockdown of Bcl-xL and Mcl-1 is sufficient to induce spontaneous apoptosis. Quinoxaline derivatives were screened for the induction of Mcl-1 dependent apoptosis using a cell line without functional Bcl-xL. Quinoxaline urea analog 1 h was able to specifically induce apoptosis in an Mcl-1 dependent manner. We demonstrate that even small changes to 1h results in dramatic loss of activity. In addition, 1 h and ABT-737 synergistically inhibit cell growth and induce apoptosis. Our results also suggest that 1h could have therapeutic potential against ABT-737 refractory cancer.

Synthesis and evaluation of macrocyclic diarylether heptanoid natural products and their analogs.

The macrocyclic diarylether heptanoid (MDEH) natural products have been used in folk medicine for centuries. MDEHs are reported to exert anti-tumor properties by inhibiting the activation of NF-κB. Here we report the synthesis of a small MDEH library (first reported synthesis of racemic platycarynol) using a Grubbs cross metathesis/Ullmann cyclization strategy. Evaluation of the library led to the identification of MDEH 9b which sensitizes pancreatic cancer cells to gemcitabine mediated growth inhibition and apoptosis.

2,3-Substituted quinoxalin-6-amine analogs as antiproliferatives: a structure-activity relationship study.

The quinoxaline core is considered a privileged scaffold as it is found in a variety of biologically relevant molecules. Here we report the synthesis of a quinoxalin-6-amine library, screening against a panel of cancer cell lines and a structure-activity relationship (SAR). This resulted in the identification of a bisfuranylquinoxalineurea analog (7c) that has low micromolar potency against the panel of cancer cell lines. We also show that cells treated with quinoxalineurea 7c results in caspase 3/7 activation, PARP cleavage and Mcl-1 dependent apoptosis.