Chemical Biology Strategy Reveals Pathway-Selective Inhibitor of NF-κB Activation Induced by Protein Kinase C

摘要

Dysregulation of NF-κB activity contributes to many autoimmune and inflammatory diseases. At least nine pathways for NF-κB activation have been identified, most of which converge on the IκB kinases (IKKs). Although IKKs represent logical targets for potential drug discovery, chemical inhibitors of IKKs suppress all known NF-κB activation pathways, and thus lack the selectivity required for safe use. A unique NF-κB 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-κB pathway induced by PKC, operating downstream of PKC but upstream of IKKβ, without inhibiting other NF-κB activation pathways. In human B cells stimulated through surface immunoglobulin, CID-2858522 inhibited NF-κB DNA-binding activity and expression of endogenous NF-κB-dependent target gene, TRAF1. Altogether, as a selective chemical inhibitor of the NF-κB pathway induced by PKC, CID-2858522 serves as a powerful research tool, and may reveal new paths towards therapeutically useful NF-κB inhibitors.