PF 184

PF-184 is a potent inhibitory factor-κB kinase 2 (IKK-2) inhibitor with an IC50 of 37 nM. PF-184 has anti-inflammatory effects[1].

Signaling Pathways >> NF-κB >> IKK

Research Areas >> Inflammation/Immunology

IKK-2:37 nM (IC50)

PF-184 has slow dissociation kinetics with a T1/2 of 6.7 h from rhIKK-2, very low oral bioavailability (5%), high intravenous clearance (59 ml/min/kg), and high P450 metabolism in human liver microsomes[1]. PF-184 binds tightly to endogenous IKK-2 and shows extended inhibition of kinase activity and cytokine production[1]. PF-184 shows a concentration-dependent inhibition on LPS- and IL-1β-induced production of inflammatory mediators in a variety of human disease-relevant cells[1]. PF-184 (0.001-10 µM, 1 h) inhibits IL-1β-induced TNF-α in a concentration-dependent manner with maximal efficacies of 94% and relative potencies of 163 nM[1]. PF-184 inhibits LPS-induced cytokine production from rat alveolar macrophages and blocked p65 nuclear translocation[1].

PF-184 (0.3-2.5 mg; i.t.; once) blocks neutrophil infiltration and BAL cell cytokine production[1]. Animal Model: Fasted male Sprague-Dawley rats (350 g) placed into a chamber connected to a large volume nebulizer filled with 20 ml of 1 mg/mL solution of LPS[1] Dosage: 0.3–2.5 mg Administration: Nano suspension and administered intratracheally in a volume of 100 µL, 60 min before aerosolized LPS Result: Resulted in a comparable attenuation of total cell and PMN cell infiltration 4 h after LPS exposure. Dose-dependently inhibited cell infiltration with EC50 values of 1 mg. Dose-dependently suppressed BAL fluid TNF- and PGE2 levels comparable with cell infiltration. Inhibited p65 translocation. Showed long-lasting activity.

[1]. Sommers CD, et al. Novel tight-binding inhibitory factor-kappaB kinase (IKK-2) inhibitors demonstrate target-specific anti-inflammatory activities in cellular assays and following oral and local delivery in an in vivo model of airway inflammation. J Pharmacol Exp Ther. 2009 Aug;330(2):377-88.