NF-κB inhibitors and activators
Related
Use this guide to find the right compound to activate or inhibit the NF-κB signaling pathway.
Multiple pharmacological compounds can activate or inhibit proteins involved in NF-kB signaling regulation. The table below highlights some of the small molecules that can be used to study the NF-kB pathway.
| Classification | Small molecule | Activity | IC50 | Ref. |
| IKK complex inhibitor | TPCA 1 | IKK inhibitor that blocks IκB degradation and IL-8 expression | 400 nM (IKKα), 17.9 nM (IKKβ) | 1,2 |
| NF-κB Activation Inhibitor VI (BOT-64) | IKKβ inhibitor and suppressor of NOS, COX-2, IL-1β, IL-6 expression | 1 μM in RAW 264.7 cells | 3 | |
| BMS 345541 | Highly selective IKKα inhibitor | 4 μM (IKKα), 0.3 µM (IKKβ) | 4 | |
| Amlexanox | IKKε and TBK-1 inhibitor with therapeutic uses | 1-2 μM (IKKε) | 5 | |
| SC-514 (GK 01140) | Selective, reversible and ATP competitive IKKβ inhibitor | 10.2 μM | 6,7 | |
| IMD 0354 | Potent, selective, IKKβ inhibitor | 250 nM | 8 | |
| IKK-16 | Potent, selective IKK inhibitor and suppressor of NOS expression | 25 nM | 9,10 | |
| IκB degradation inhibitor | BAY 11-7082 | Inhibits ubiquitin conjugating ligases | 10 μM | 11,12 |
| MG-115 | Potent, reversible proteasome inhibitor disrupts RANKL signaling | 97.5 nM | 13,14 | |
| MG-132 | 22.4 nM | 14 | ||
| Lactacystin | Potent, irreversible, selective 20S proteasome inhibitor | 0.2-2.8 μM | 15 | |
| Epoxomicin | 6.8 nM | 14 | ||
| Parthenolide | Inhibits IκBα degradation and IKK complex activity | 30 μM | 12 | |
| Carfilzomib | Potent, irreversible 26S proteasome inhibitor | 8.32-16.55 nM | 16 | |
| MLN-4924 (Pevonedistat) | Modulates a ubiquitin-like protein (Nedd-8) activating enzyme | 4.7 nM | 17,18 | |
| NF-κB nuclear translocation inhibitor | JSH-23 | Exhibits translocation inhibition in vivo and in LPS-induced RAW264.7 cells | - | 19,20 |
| Rolipram | Exhibits translocation inhibition in LPS-induced chorionic cells | - | 21 | |
| p65 acetylation inhibitor | Gallic acid | Prevents p65 acetylation in LPS-induced A549 cells | 76 μM | 22,34 |
| Anacardic acid | Inhibits p65 acetylation in TNF-induced KBM-5 cells (at 4 µM) | - | 23 | |
| NF-κB-DNA binding | GYY 4137 | Reduces NF-κB binding to RANTES and IL-8 promoter | - | 24 |
| p-XSC | Inhibits NF-κB binding by covalent modification of p50 Cys62 | 500 nM | 25 | |
| CV 3988 | PAFR antagonist that inhibits p65 DNA binding | - | 26 | |
| Prostaglandin E2 (PGE2) | Dissociates nuclear trafficking of p50-p65 subunits | - | 27 | |
| NF-κB transactivation inhibitor | LY 294002 | Blocks NF-κB-dependent transactivation following IL-1 stimulation | - | 28,29 |
| Wortmannin | ||||
| Mesalamine | Blocks p65-dependent transactivation | - | 30 | |
| p53 induction | Quinacrine | Downregulates NF-κB and downstream transcriptional targets | 5 μM (RKO cells) | 31,32 |
| Flavopiridol | Inhibits TNFα-induced NF-κB activation | 1 μM (HT29 cells) | 33 | |
| NF-κB activators & inducers | Betulinic acid | Increases NF-κB translocation (p65) and transcriptional activity | - | 35 |
| Prostratin | Induces activation of NF-κB synergistically with calcineurin | - | 36 | |
| PMA | Activates and induces NF-κB DNA binding | - | 37,38 | |
| Calcimycin (A23187) | Ca2+ ionophore and activator of NF-κB | - | 39 |
Antioxidants
Antioxidants such as PDTC40 and NAC41 have shown a potential to inhibit NF-κB activation either by exogeneous induction (e.g. LPS, TNFα) or hydrogen peroxide treatment. Antioxidants are likely to inhibit NF-κB by scavenging reactive oxygen intermediates involved in the NF-κB pathway42.
Anti-inflammatory and immunosuppressant drugs
The commonly available NSAID, sodium salicylate was shown to bind IKKβ43 and inhibit proteasome activity44 potentially reducing IκB degradation. A potent immunomodulatory glucocorticoid steroid, dexamethasone (DEX) exhibited interference with NF-κB activation and reduced TNFα production45,46.
Investigations into immunosuppressant drugs revealed cyclosporin A (CsA) to inhibit NF-κB /RelA activation and block IL-2 and IL-8 gene expression47,48. FK506 (tacrolimus) another commercially available immunosuppressive drug blocks p50 nuclear translocation thereby reducing activation of its subsequent promoters and gene expression of inflammatory cytokines such as IL-249.
References
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