IKK (IκB kinase) is an enzyme complex that is the core element of the NF-κB cascade. The complex has two kinases (IKKα and IKKβ) and a regulatory subunit, NEMO/IKKγ. IKKα and IKKβ show a similar structure (50% sequence identity), and include an amino-terminal kinase domain, a helix-loop-helix that functions in modulating IKK kinase activity, and a leucine zipper. IKK is the signal integration hub for NF-κB activation. Specifically, IKK can phosphorylate IκBα, which results in ubiquitination and dissociation of IκBα from NF-κB, and eventually leading to activation of the transcription factor NF-κB. Therefore, IKKs are therapeutic targets due to their crucial roles in various biological processes, including the immune response, the stress response, and tumor development.
The inhibitor of IKK2 (IKKβ) is one of the important kinases in inflammation. Inhibition of IKK2 has been a therapeutic strategy for inflammatory and autoimmune diseases. Importantly, IKK2 plays a significant role in brain cells following a stroke. If NF-κB activation by IKK2 is blocked, damaged cells within the brain stay alive. Additionally, blockade of IKK2 can reduce the size of an infarct, or tissue killed or damaged by ischemia in mice.
PF-184 is a potent and selective IKK2 inhibitor.
PF-184 shows selectivity for IKK2 (IC50=37 nM) over rhIKK1, IKKi, and more than 30 tyrosine and serine/threonine kinases. Importantly, PF-184 broadly inhibits IKK2-dependent inflammatory products in human disease-relevant cells (such as PBMC, neutrophils, airway epithelial cells, and airway endothelial cells). Meanwhile, PF-184 administration by intratracheal dose-dependently inhibits neutrophil infiltration and BAL cell cytokine production in rat airway inflammation models. Thus, PF-184 has the potential for the research of inflammation, such as asthma and chronic obstructive pulmonary disease.
All in all, PF-184 is a potent and selective IKK2 inhibitor that has the potential for the research of inflammation.