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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.
|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|
|Lactacystin||Potent, irreversible, selective 20S proteasome inhibitor||0.2-2.8 μM||15|
|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|
|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 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.
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