A selective novel low‐molecular‐weight inhibitor of IκB kinase‐β (IKK‐β) prevents pulmonary inflammation and shows broad anti‐inflammatory activity

Pulmonary inflammatory diseases such as asthma are characterized by chronic, cell‐mediated inflammation of the bronchial mucosa. Recruitment and activation of inflammatory cells is orchestrated by a variety of mediators such as cytokines, chemokines, or adhesion molecules, the expression of which is regulated via the transcription factor nuclear factor kappa B (NF‐ κ B). NF‐ κ B signaling is controlled by the inhibitor of kappa B kinase complex (IKK), a critical catalytic subunit of which is IKK‐ β . We identified COMPOUND A as a small‐molecule, ATP‐competitive inhibitor selectively targeting IKK‐ β kinase activity with a K i value of 2 n M . COMPOUND A inhibited stress‐induced NF‐ κ B transactivation, chemokine‐, cytokine‐, and adhesion molecule expression, and T‐ and B‐cell proliferation. COMPOUND A is orally bioavailable and inhibited the release of LPS‐induced TNF‐ α in rodents. In mice COMPOUND A inhibited cockroach allergen‐induced airway inflammation and hyperreactivity and efficiently abrogated leukocyte trafficking induced by carrageenan in mice or by ovalbumin in a rat model of airway inflammation. COMPOUND A was well tolerated by rodents over 3 weeks without affecting weight gain. Furthermore, in mice COMPOUND A suppressed edema formation in response to arachidonic acid, phorbol ester, or edema induced by delayed‐type hypersensitivity. These data suggest that IKK‐ β inhibitors offer an effective therapeutic approach for inhibiting chronic pulmonary inflammation. British Journal of Pharmacology (2005) 145 , 178–192. doi: 10.1038/sj.bjp.0706176