The nuclear factor-κB (NF-κB) plays an important role in inflammatory and immune responses. Aberrant NF-κB signaling is implicated in multiple disorders, including cancer. Targeting the regulatory scaffold subunit IκB kinase γ (IKKγ/NEMO) as therapeutic interventions could be promising due to its specific involvement in canonical NF-κB activation without interfering with non-canonical signaling. In this study, the use of unnatural amino acid substituted IKKβ with unique photophysical activity to sense water environment changes upon interaction with NEMO provides a powerful in vitro screening platform that would greatly facilitate the identification of compounds having the potential to disrupt IKKβ-NEMO interaction, and thus specifically modulate the canonical NF-κB pathway. We then utilized a competitive binding platform to screen the binding ability of a number of potential molecules being synthesized. Our results suggest that a lead compound (−)-PDC-099 is a potent agent with ascertained potency to disrupt IKKβ-NEMO complex for modulating NF-κB canonical pathway.

核因子-κB（NF-κB）在炎症和免疫反应中起重要作用。异常的NF-κB信号传导与多种疾病有关，包括癌症。靶向调节支架亚基IκB激酶γ（IKKγ/ NEMO）作为治疗干预措施可能是有希望的，因为它特异性参与了经典的NF-κB激活而不会干扰非经典的信号传导。在这项研究中，使用具有独特光物理活性的非天然氨基酸取代的IKKβ来感知与NEMO相互作用后水环境的变化提供了强大的体外方法筛选平台，将大大有助于鉴定具有破坏IKKβ-NEMO相互作用的潜力的化合物，从而特异性调节规范的NF-κB途径。然后，我们利用竞争性结合平台来筛选正在合成的许多潜在分子的结合能力。我们的结果表明，先导化合物（-）-PDC-099是一种有效药剂，具有确定的能力来破坏IKKβ-NEMO复合物，从而调节NF-κB的经典途径。