Nuclear factor-kB (NF-kB)/Rel transcription factors are known to play a pivotal role in inflammatory diseases. Aberrant regulation of NF-kB is also observed in autoimmune disorders and in different types of cancers. Hence, the signaling pathways leading to the regulation of NF-kB activity have become a focal point for drug discovery efforts. NF-kB is normally sequestered in the cytoplasm of non-stimulated cells and consequently must be translocated into the nucleus to function. The subcellular localization of NF-kB is controlled by a family of inhibitory proteins known as IkBs, which bind to NF-kB and mask its nuclear localization signal thereby preventing its uptake into the nucleus.

The activation of the NF-kB by the extracellular inducers depends on the phosphorylation and subsequent degradation of IkB inhibitor proteins (IkBa, -b, -e ,-g, p105, and p100). Activation of NF-kB is achieved through the action of a family of serine/threonine kinases known as IkB kinase ( IKK). IKK contains two catalytic subunits (IKKa and IKKb) and a regulatory/adapter protein NEMO (also known as IKKg). IKKa and IKKb phosphorylate IkB proteins and the members of the NF-kB family. All IkB proteins contain two conserved serine residues within their N-terminal region, which are phosphorylated by IKK. IKKa and IKKb share about 50% sequence homology and can interchangeably phosphorylate Ser³²/Ser³⁶ of IkBa , and Ser¹⁹/Ser²³ of IkBb . These phosphorylation events lead to the immediate polyubiquitination of IkB proteins and rapid degradation by the proteasomal pathway. Hence, inhibitors of IKK have long been sought as specific regulators of NF-kB.

IKK Inhibitor II, Wedelolactone, Cat. No. 401474
The naturally isolated active ingredient of the herbal medicine, Eclipta alba, that acts as a cell permeable, selective and irreversible inhibitor of IKKa and b kinase activity (IC₅₀ < 10 mM). Inhibits NF-kB-mediated gene transcription in cells by blocking the phosphorylation and degradation of IkBa . Has no effects on p38 MAP kinase or Akt. Purity: ≥ 98% by HPLC

IKK Inhibitor III, BMS-345541 Cat. No. 401480
A cell-permeable quinoxaline compound that displays anti-inflammatory properties. Acts as a potent, selective, and allosteric site-binding inhibitor of IKK-2 (IC₅₀ ~300 nM). Exhibits ~10-fold greater selectivity over IKK-1 (IC₅₀ ~ 4 mM) and no activity towards IKKe and a panel of more than 15 unrelated protein kinases even at concentrations as high as 100 mM. Inhibits cellular IkBa phosphorylation (IC₅₀ = 4 mM in THP-1 cells) and LPS-induced cytokine production both in vitro (IC₅₀ = 1-5 mM in THP-1 cells) and in vivo (IC₅₀ = 10 mg/kg in mice). Effectively blocks inflammation and joint destruction in a murine arthritis model. Purity: ≥96% by HPLC.

NEW! IKK-2 Inhibitor VIII, Cat. No. 401487
A cell-permeable piperidinyl-pyridine compound that acts as a selective inhibitor of IKK-2 activity (IC₅₀ = 8.5 and 250 nM for IKK-2 and IKK-1, respectively) with little effect towards IKK-3, Syk, and MKK4 (IC₅₀ >20 mM). Exhibits good aqueous solubility (0.12 mg/ml in pH 7.4 isotonic buffer) and potent activity in various cellular assays in vitro (IC₅₀ <150 nM). Shown to be orally bioavailable both in rats and mice (BA = 60% and 16%, respectively) and effectively inhibit arachidonic acid-induced swelling in a murine ear edema model in vivo. Purity: ≥95% by HPLC.

NF- kB Activation Inhibitor II, JSH-23 Cat. No. 481408
A cell-permeable diamino compound that selectively blocks nuclear translocation of NF-kB p65 and its transcription activity (IC₅₀ = 7.1 mM in a NF-kB reporter assay using RAW 264.7) without affecting IkB degradation. Shown to suppress DNA-binding of NF-kB and downregulate LPS-induced gene expression and apoptotic chromatin condensation. Purity: ≥ 95% by HPLC

NEW! NF-kB Activation Inhibitor IV, Cat. No. 481412
A cell-permeable trans-stilbene Resveratrol (Cat. No. 554325) analog that exhibits much enhanced anti-inflammatory potency, but no anti-oxidant activity. Suppresses LPS-induced COX-2 mRNA expression in BV-2 cells (~46% inhibition at 150 nM) and Shown to be ~130-fold more potent than Resveratrol in inhibiting TNF-a -stimulated NF-kB reporter activity in 293T cells (IC₅₀ = 150 nM). Purity: ≥98% by HPLC.

Withaferin A, Withania somnifera Cat. No. 681535
A cell-permeable steroidal lactone that displays antitumor, anti-inflammatory, radiosensitizing, and immunosuppressive properties. Potently inhibits angiogenesis both in vitro (IC₅₀ = 12 nM against HUVEC proliferation) and in vivo (80% inhibition at 7 mg/kg/day in C57BL/6J mice, s.c.) and NF-kB activation (IC₅₀ = 500 nM in TNF-a -induced endothelial cells) by targeting the ubiquitin-mediated proteasome pathway. At higher concentrations (~5 mM) also affects AP-1 transcription and induces cell death. Purity: ≥ 94% by HPLC. RTECS KE7288500, CAS 5119-48-2.