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

1 Pulmonary inflammatory diseases such as asthma are characterized by chronic, cell‐mediated inflammation of the bronchial mucosa. 2 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). 3 NF‐ κ B signaling is controlled by the inhibitor of kappa B kinase complex (IKK), a critical catalytic subunit of which is IKK‐ β . 4 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 . 5 COMPOUND A inhibited stress‐induced NF‐ κ B transactivation, chemokine‐, cytokine‐, and adhesion molecule expression, and T‐ and B‐cell proliferation. 6 COMPOUND A is orally bioavailable and inhibited the release of LPS‐induced TNF‐ α in rodents. 7 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. 8 COMPOUND A was well tolerated by rodents over 3 weeks without affecting weight gain. 9 Furthermore, in mice COMPOUND A suppressed edema formation in response to arachidonic acid, phorbol ester, or edema induced by delayed‐type hypersensitivity. 10 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