| A selective novel low-molecular-weight inhibitor of IκB kinase-β (IKK-β) prevents pulmonary inflammation and shows broad anti-inflammatory activity | |||||||||||
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| 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-κB).NF-κB 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 Ki value of 2 nM.COMPOUND A inhibited stress-induced NF-κB 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. | |||||||||||
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