Chemical Biology Strategy Reveals Pathway-Selective Inhibitor of NF-κB Activation Induced by Protein Kinase C
| Autor: | Shinichi Kitada, Nicholas D. P. Cosford, Gregory P. Roth, Eric Dudl, Ying Su, John R. Cashman, Satyamaheshwar Peddibhotla, Andrew Hurder, Michael Cuddy, Daniel Re, Layton H. Smith, Karl J. Okolotowicz, Thomas J. Kipps, John C. Reed, Ranxin Shi, Russell Dahl |
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| Rok vydání: | 2010 |
| Předmět: |
TRAF1
Chemical biology Biology Biochemistry Jurkat cells Article Cell Line Small Molecule Libraries Jurkat Cells Mice Growth factor receptor Animals Humans Protein Kinase C Protein kinase C Cell Proliferation B-Lymphocytes Drug discovery Kinase NF-kappa B General Medicine I-kappa B Kinase Cell biology Immunoglobulin M Cell culture Interleukin-2 Molecular Medicine Benzimidazoles Signal Transduction |
| Zdroj: | ACS Chemical Biology. 5:287-299 |
| ISSN: | 1554-8937 1554-8929 |
| DOI: | 10.1021/cb9003089 |
| Popis: | Dysregulation of NF-kappaB activity contributes to many autoimmune and inflammatory diseases. At least nine pathways for NF-kappaB activation have been identified, most of which converge on the IkappaB kinases (IKKs). Although IKKs represent logical targets for potential drug discovery, chemical inhibitors of IKKs suppress all known NF-kappaB activation pathways and thus lack the selectivity required for safe use. A unique NF-kappaB 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-kappaB pathway induced by PKC, operating downstream of PKC but upstream of IKKbeta, without inhibiting other NF-kappaB activation pathways. In human B cells stimulated through surface immunoglobulin, CID-2858522 inhibited NF-kappaB DNA-binding activity and expression of endogenous NF-kappaB-dependent target gene, TRAF1. Altogether, as a selective chemical inhibitor of the NF-kappaB pathway induced by PKC, CID-2858522 serves as a powerful research tool and may reveal new paths toward therapeutically useful NF-kappaB inhibitors. |
| Databáze: | OpenAIRE |
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