All tags Agonists activators antagonists and inhibitors NF-κB inhibitors and activators

NF-κB inhibitors and activators

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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.​

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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
Wortmannin
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

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.


References

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2. Dondelinger, Y. et al. NF-κB-independent role of IKKα/IKKβ in preventing RIPK1 kinase-dependent apoptotic and necroptotic cell death during TNF signaling. Mol. Cell 60, 63–76 (2015).

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).

5. Larsen, M. J. et al. The role of HTS in drug discovery at the University of Michigan. Comb. Chem. High Throughput Screen. 17, 210–30 (2014).

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).

15. Vigneron, N., Abi Habib, J. & Van den Eynde, B. J. The capture proteasome assay (CAPA) to evaluate subtype-specific proteasome inhibitors. Data Br. 4, 146–51 (2015).

16. Crawford, L. J. et al. Synergistic effects of proteasome inhibitor carfilzomib in combination with tyrosine kinase inhibitors in imatinib-sensitive and -resistant chronic myeloid leukemia models. Oncogenesis 3, e90 (2014).

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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