Discovery of Novel Small-molecule Inhibitors of Nuclear Factor-κB Signaling with Anti-inflammatory and Anti-cancer Properties.

Excessive NF-KB activation contributes to the pathogenesis of numerous diseases. Small-molecule inhibitors of NF-KB signaling have significant therapeutic potential especially in treating inflammatory diseases and cancers. In this study, we performed a cell-based high-throughput screening to discover novel agents capable of inhibiting NF-KB signaling. On the basis of two hit scaffolds from the screening, we synthesized 69 derivatives to optimize the potency for inhibition of NF-KB activation, leading to successful discovery of the most potent compound Z9j with over 170-fold enhancement of inhibitory activity. Preliminary mechanistic studies revealed that Z9j inhibited NF-KB signaling via suppression of Src/Syk, PI3K/Akt, and IKK/IKB pathways. This novel compound also demonstrated antiinflammatory and anticancer activities, warranting its further development as a potential multifunctional agent to treat inflammatory diseases and cancers.