Screening of novel small molecule inhibitors of NF‐κB activation in lung cancer

Abstract

Lung cancer is the leading cause of cancer deaths in the United States. Inflammation of the lung resulting from exposure to cigarette smoke and other contributors may exacerbate the initiation, promotion, and development of lung cancer. Nuclear factor‐κB (NF‐κB) is a key transcription factor involved in both inflammation and cancer. NF‐κB remains inactive when sequestered in the cytoplasm by IκB. Activating signals release NF‐κB, allowing translocation to the nucleus. Nuclear NF‐κB initiates transcription of genes related to proliferation, chronic inflammation, and blockage of apoptosis.Curcumin, a natural product, has been shown to inhibit NF‐κB activation; however, lack of adequate solubility and oral bioavailability reduce its therapeutic potential. Our goal was to identify novel small molecule inhibitors of NF‐κB activation using an image‐based high content screening (HCS) assay for monitoring NF‐κB nuclear translocation. Initial drug discovery efforts screened a small compound library for efficacy in A549 lung cancer cells. This campaign identified promising candidate compounds for animal studies. Large scale HCS resulted in potent compounds that effectively block nuclear translocation of NF‐κB. Selected compounds are under investigation.Research support provided by the US National Institutes of Health grants P01 CA116676.