NF-κB inhibitors and activators


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 NF-kB pathway.​


ClassificationSmall moleculeActivityIC50Ref.
IKK complex inhibitorTPCA 1IKK inhibitor that blocks IκB degradation and IL-8 expression400 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 expression1 μM in RAW 264.7 cells3
BMS 345541Highly selective IKKα inhibitor4 μM (IKKα), 0.3 µM (IKKβ)4
AmlexanoxIKKε and TBK-1 inhibitor with therapeutic uses1-2 μM (IKKε)5
SC-514 (GK 01140)Selective, reversible and ATP competitive IKKβ inhibitor10.2 μM6,7
IMD 0354Potent, selective, IKKβ inhibitor 250 nM8
IKK-16Potent, selective IKK inhibitor and suppressor of NOS expression25 nM9,10
IκB degradation inhibitorBAY 11-7082Inhibits ubiquitin conjugating ligases10 μM11,12
MG-115Potent, reversible proteasome inhibitor disrupts RANKL signaling97.5 nM13,14
MG-13222.4 nM14
LactacystinPotent, irreversible, selective 20S proteasome inhibitor0.2-2.8 μM15
Epoxomicin6.8 nM14
ParthenolideInhibits IκBα degradation and IKK complex activity30 μM12
CarfilzomibPotent, irreversible 26S proteasome inhibitor 8.32-16.55 nM16
MLN-4924 (Pevonedistat)Modulates a ubiquitin-like protein (Nedd-8) activating enzyme4.7 nM17,18
NF-κB nuclear translocation inhibitorJSH-23Exhibits translocation inhibition in vivo and in LPS-induced RAW264.7 cells-19,20
RolipramExhibits translocation inhibition in LPS-induced chorionic cells-21
p65 acetylation inhibitorGallic acidPrevents p65 acetylation in LPS-induced A549 cells76 μM22,34
Anacardic acidInhibits p65 acetylation in TNF-induced KBM-5 cells (at 4 µM)-23
NF-κB-DNA binding GYY 4137Reduces NF-κB binding to RANTES and IL-8 promoter-24
p-XSCInhibits NF-κB binding by covalent modification of p50 Cys62500 nM25
CV 3988PAFR antagonist that inhibits p65 DNA binding-26
Prostaglandin E2 (PGE2)Dissociates nuclear trafficking of p50-p65 subunits-27
NF-κB transactivation inhibitorLY 294002Blocks NF-κB-dependent transactivation following IL-1 stimulation-28,29
MesalamineBlocks p65-dependent transactivation-30
p53 induction QuinacrineDownregulates NF-κB and downstream transcriptional targets5 μM (RKO cells)31,32
FlavopiridolInhibits TNFα-induced NF-κB activation1 μM (HT29 cells)33
NF-κB activators & inducersBetulinic acidIncreases NF-κB translocation (p65) and transcriptional activity-35
ProstratinInduces activation of NF-κB synergistically with calcineurin-36
PMAActivates 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 potential to inhibit NF-κB activation either by exogeneous induction (e.g. LPS, TNFα) or hydrogen peroxide treatment. Antioxidants are likely 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 expression47,48FK506 (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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3. Kim, B. H. et al. Benzoxathiole derivative blocks lipopolysaccharide-induced nuclear factor-kappaB activation and nuclear factor-kappaB-regulated gene transcription through inactivating inhibitory kappaB kinase beta. Mol. Pharmacol. 73, 1309–1318 (2008).

4. Burke, J. R. et al. BMS-345541 is a highly selective inhibitor of IκB kinase that binds at an allosteric site of the enzyme and blocks NF-κB-dependent transcription in mice. J. Biol. Chem. 278, 1450–1456 (2003).

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6. Kishore, N. et al. A selective IKK-2 inhibitor blocks NF-κB-dependent gene expression in interleukin-1β-stimulated synovial fibroblasts. J. Biol. Chem. 278, 32861–32871 (2003).

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8. Ogawa, H. et al. IκB kinase β inhibitor IMD-0354 suppresses airway remodelling in a Dermatophagoides pteronyssinus-sensitized mouse model of chronic asthma. Clin. Exp. Allergy 41, 104–115 (2011).

9. Coldewey, S. M., Rogazzo, M., Collino, M., Patel, N. S. A. & Thiemermann, C. Inhibition of IκB kinase reduces the multiple organ dysfunction caused by sepsis in the mouse. Dis. Model. Mech. 6, 1031–1042 (2013).

10. Waelchli, R. et al. Design and preparation of 2-benzamido-pyrimidines as inhibitors of IKK. Bioorganic Med. Chem. Lett. 16, 108–112 (2006).

11. Strickson, S. et al. The anti-inflammatory drug BAY 11-7082 suppresses the MyD88-dependent signalling network by targeting the ubiquitin system. Biochem. J 451, 427–437 (2013).

12. Ghashghaeinia, M. et al. The NFκB pathway inhibitors bay 11-7082 and parthenolide induce programmed cell death in anucleated erythrocytes. Cell. Physiol. Biochem. 27, 45–54 (2011).

13. Katsuyama, K., Shichiri, M., Marumo, F. & Hirata, Y. NO inhibits cytokine-induced iNOS expression and NF-kappaB activation by interfering with phosphorylation and degradation of IkappaB-alpha. Arter. Thromb. Vasc. Biol. 18, 1796–1802 (1998).

14. Kreidenweiss, A., Kremsner, P. G. & Mordmüller, B. Comprehensive study of proteasome inhibitors against Plasmodium falciparum laboratory strains and field isolates from Gabon. Malar. J. 7, 187 (2008).

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17. Godbersen, J. C. et al. The Nedd8-activating enzyme inhibitor MLN4924 thwarts microenvironment-driven NF-kappaB activation and induces apoptosis in chronic lymphocytic leukemia B cells. Clin. Cancer Res. 20, 1576–1589 (2014).

18. Curtis, V. F. et al. Stabilization of HIF through inhibition of Cullin-2 neddylation is protective in mucosal inflammatory responses. FASEB J. 29, 208–215 (2015).

19. Kumar, A., Negi, G. & Sharma, S. S. JSH-23 targets nuclear factor-kappa B and reverses various deficits in experimental diabetic neuropathy: Effect on neuroinflammation and antioxidant defence. Diabetes, Obes. Metab. 13, 750–758 (2011).

20. Shin, H. M. et al. Inhibitory action of novel aromatic diamine compound on lipopolysaccharide-induced nuclear translocation of NF-κB without affecting IκB degradation. FEBS Lett. 571, 50–54 (2004).

21. Herve, R. et al. The PDE4 inhibitor rolipram prevents NF-kappa B binding activity and proinflammatory cytokine release in human chorionic cells. J. Immunol. (Baltimore, Md. : 1950) 181, 2196–2202 (2008).

22. Choi, K.-C. et al. Gallic acid suppresses lipopolysaccharide-induced nuclear factor-κB signaling by preventing RelA acetylation in A549 lung cancer cells. Mol. Cancer Res. 7, 2011–2021 (2009).

23. Sung, B. et al. Anacardic acid (6-nonadecyl salicylic acid), an inhibitor of histone acetyltransferase, suppresses expression of nuclear factor-κB–regulated gene products involved in cell survival, proliferation, invasion, and inflammation through inhibition of the inhib. Blood 111, 4880 LP-4891 (2008).

24. Li, H. et al. Role of hydrogen sulfide in paramyxovirus infections. J. Virol. 89, 5557–68 (2015).

25. Chen, K. M. et al. Inhibition of nuclear factor-kappa B DNA binding by organoselenocyanates through covalent modification of the p50 subunit. Cancer Res. 67, 10475–10483 (2007).

26. Ogbozor, U. D., Opene, M., Renteria, L. S., McBride, S. & Ibe, B. O. Mechanism by which nuclear factor-kappa beta (NF-kB) regulates ovine fetal pulmonary vascular smooth muscle cell proliferation. Mol. Genet. Metab. Reports 4, 11–18 (2015).

27. Gomez, P. F. et al. Resolution of inflammation: prostaglandin E2 dissociates nuclear trafficking of individual NF-kappaB subunits (p65, p50) in stimulated rheumatoid synovial fibroblasts. J. Immunol. 175, 6924–6930 (2005).

28. Young, H. K., Choi, K. H., Park, J. W. & Taeg, K. K. LY294002 inhibits LPS-induced NO production through a inhibition of NF-κB activation: Independent mechanism of phosphatidylinositol 3-kinase. Immunol. Lett. 99, 45–50 (2005).

29. Manna, S. K. & Aggarwal, B. B. Wortmannin inhibits activation of nuclear transcription factors NF-kappaB and activated protein-1 induced by lipopolysaccharide and phorbol ester. FEBS Lett. 473, 113–118 (2000).

30. Bantel, H. et al. Mesalazine inhibits activation of transcription factor NF-kappa B in inflamed mucosa of patients with ulcerative colitis. Am. J. Gastroenterol. 95, 3452–7 (2000).

31. Gurova, K. V et al. Small molecules that reactivate p53 in renal cell carcinoma reveal a NF-kappaB-dependent mechanism of p53 suppression in tumors. Proc. Natl. Acad. Sci. U. S. A. 102, 17448–53 (2005).

32. Jani, T. S., DeVecchio, J., Mazumdar, T., Agyeman, A. & Houghton, J. a. Inhibition of NF-kappaB signaling by quinacrine is cytotoxic to human colon carcinoma cell lines and is synergistic in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or oxaliplatin. J. Biol. Chem. 285, 19162–19172 (2010).

33. Takada, Y. & Aggarwal, B. B. Flavopiridol inhibits NF-κB activation induced by various carcinogens and inflammatory agents through inhibition of IκBα kinase and p65 phosphorylation. Abrogation of cyclin D1, cyclooxygenase-2, and matrix metalloprotease-9. J. Biol. Chem. 279, 4750–4759 (2004).

34. Morais, M. C. C. et al. Suppression of TNF-α induced NFκB activity by gallic acid and its semi-synthetic esters: possible role in cancer chemoprevention. Nat. Prod. Res. 24, 1758–65 (2010).

35. Kasperczyk, H. et al. Betulinic acid as new activator of NF-kappaB: molecular mechanisms and implications for cancer therapy. Oncogene 24, 6945–56 (2005).

36. Chan, J. K., Bhattacharyya, D., Lassen, K. G., Ruelas, D. & Greene, W. C. Calcium/calcineurin synergizes with prostratin to promote NF-κB dependent activation of latent HIV. PLoS One 8, e77749 (2013).

37. Holden, N. S. et al. Phorbol ester-stimulated NF-kappaB-dependent transcription: roles for isoforms of novel protein kinase C. Cell. Signal. 20, 1338–1348 (2008).

38. Busuttil, V. et al. Blocking NF-kappaB activation in Jurkat leukemic T cells converts the survival agent and tumor promoter PMA into an apoptotic effector. Oncogene 21, 3213–3224 (2002).

39. Ggandison, L., Nolan, G. P. & Pfaff, D. W. Activation of the transcription factor NF-κB in GH3 pituitary cells. Mol. Cell. Endocrinol. 106, 9–15 (1994).

40. Schreck, R., Meier, B., Männel, D. N., Dröge, W. & Baeuerle, P. A. Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. J. Exp. Med. 175, 1181–94 (1992).

41. Oka, S., Kamata, H., Kamata, K., Yagisawa, H. & Hirata, H. N-acetylcysteine suppresses TNF-induced NF-kappaB activation through inhibition of IkappaB kinases. FEBS Lett. 472, 196–202 (2000).

42. Gupta, S., Sundaram, C., Reuter, S. & Aggarwal, B. Inhibiting NF-kB Activation by Small Molecules As a Therapeutic Strategy. Biochim. Biophys. Acta 1799, 775–787 (2011).

43. Kopp, E. & Ghosh, S. Inhibition of NF-kappa B by sodium salicylate and aspirin. Science 265, 956–9 (1994).

44. Dikshit, P., Chatterjee, M., Goswami, A., Mishra, A. & Jana, N. R. Aspirin induces apoptosis through the inhibition of proteasome function. J. Biol. Chem. 281, 29228–29235 (2006).

45. Crinelli, R. et al. Selective inhibition of NF-kB activation and TNF-alpha production in macrophages by red blood cell-mediated delivery of dexamethasone. Blood Cells. Mol. Dis. 26, 211–222 (2000).

46. Chang, C. K., Llanes, S. & Schumer, W. Effect of dexamethasone on NF-kB activation, tumor necrosis factor formation, and glucose dyshomeostasis in septic rats. J. Surg. Res. 72, 141–145 (1997).

47. Nishiyama, S. et al. Cyclosporin A inhibits the early phase of NF-??B/RelA activation induced by CD28 costimulatory signaling to reduce the IL-2 expression in human peripheral T cells. Int. Immunopharmacol. 5, 699–710 (2005).

48. Meyer, S., Kohler, N. G. & Joly, A. Cyclosporine A is an uncompetitive inhibitor of proteasome activity and prevents NF-??B activation. FEBS Lett. 413, 354–358 (1997).

49. Venkataraman, L., Burakoff, S. J. & Sen, R. J. Fk506 inhibits antigen receptor-mediated induction of C-Rel in B-lymphoid and T-lymphoid cells. J. Exp. Med. 181, 1091–1099 (1995).

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