| |
[摘要]：Dysregulation of NF-kappa B activity contributes to many autoimmune and inflammatory diseases. At least nine pathways for NF-kappa B activation have been identified, most of which converge on the I kappa B kinases (IKKs). Although IKKs represent logical targets for potential drug discovery, chemical inhibitors of IKKs suppress all known NF-kappa B activation pathways and thus lack the selectivity required for safe use. A unique NF-kappa B activation pathway is initiated by protein kinase C (PKC) that is stimulated by antigen receptors and many growth factor receptors. Using a cell-based high-throughput screening (HTS) assay and chemical biology strategy, we identified a 2-aminobenzimidazole compound, CID-2858522, which selectively inhibits the NF-kappa B pathway induced by PKC, operating downstream of PKC but upstream of IKK beta, without inhibiting other NF-kappa B activation pathways. In human B cells stimulated through surface immunoglobulin, CID-2858522 inhibited NF-kappa B DNA-binding activity and expression of endogenous NF-kappa B-dependent target gene, TRAF1. Altogether, as a selective chemical inhibitor of the NF-kappa B pathway induced by PKC, CID-2858522 serves as a powerful research tool and may reveal new paths toward therapeutically useful NF-kappa B inhibitors. |
|
