Excessive NF-κB activation contributes to the pathogenesis of numerous diseases. Small-molecule inhibitors of NF-κB 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-κB signaling. On the basis of two hit scaffolds from the screening, we synthesized 69 derivatives to optimize the potency for inhibition of NF-κB 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-κB signaling via suppression of Src/Syk, PI3K/Akt, and IKK/IκB 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.

中文翻译：

---

具有抗炎和抗癌特性的新型小分子NF-κB信号抑制剂的发现

NF-κB过度活化导致多种疾病的发病机理。NF-κB信号的小分子抑制剂具有显着的治疗潜力，尤其是在治疗炎症性疾病和癌症方面。在这项研究中，我们进行了基于细胞的高通量筛选，以发现能够抑制NF-κB信号传导的新型药物。在筛选的两个命中支架的基础上，我们合成了69种衍生物，以优化抑制NF-κB活化的能力，从而成功发现了最有效的化合物Z9j，其抑制活性增强了170倍以上。初步的力学研究表明Z9j通过抑制Src / Syk，PI3K / Akt和IKK /IκB途径来抑制NF-κB信号传导。该新型化合物还显示出抗炎和抗癌活性，使其作为治疗炎性疾病和癌症的潜在多功能剂得以进一步发展。