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

Abstract

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-kB). 3 NF-kB signaling is controlled by the inhibitor of kappa B kinase complex (IKK), a critical catalytic subunit of which is IKK-b. 4 We identified COMPOUND A as a small-molecule, ATP-competitive inhibitor selectively targeting IKK-b kinase activity with a K i value of 2 nM. 5 COMPOUND A inhibited stress-induced NF-kB 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-a 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-b inhibitors offer an effective therapeutic approach for inhibiting chronic pulmonary inflammation.

NF-κB Signaling Pathway, Inflammation and Colorectal Cancer

“…Several agents have been implemented to inhibit IKK/NF-B activity, because of the relevance of this process in cancer and those related with inflammation, such as curcumin, ginseng extract, resveratrol, green tea extract have anti-inflammatory and antiproliferative propertiese (87). Proteosome inhibitors regulates the degradation of IB and hence inhibits NFB, and a few publications have documented their efficacy in triggering apoptosis in cancer cell lines in combination with either chemotherapeiutic drugs or death-inducing cytokines (88)(89)(90). Sulfasalazine and methotrexate are widely used for treatment of acute states of IBD by inhibiting NF-B activation (91,92), thus, may also decrease the risk of developing cancer.…”

The NF-κB-mediated control of the JNK cascade in the antagonism of programmed cell death in health and disease

“…This issue will likely be addressed in part by the introduction of more selective blockers of NF-kB activation, such as IKKb inhibitors -which are currently being tested in vitro and in preclinical trials. 16,141,142 These agents will also be likely to exert their pharmacological effects by inhibiting infiltrating inflammatory cells, an important source of tumor growth factors, 4,16,38 and be effective especially when used in combination with radiation and/or standard chemotherapeutic drugs. 3,16,43,44 Yet, it should be cautioned that, even with drugs that are highly specific for the NF-kB pathway, serious side effects beyond those caused by immunosuppression are likely to arise, particularly upon chronic use.…”

Effects of IKK inhibitor PS1145 on NF-κB function, proliferation, apoptosis and invasion activity in prostate carcinoma cells

“…Thus, IKKs, especially IKKb that is critical for NF-kB activation, represent a novel important target for NFkB blockage in PC and other tumor cells. Very recently, several pharmaceutical companies have started working on the design of potent orally active IKKb inhibitors (Burke et al, 2003;Kishore et al, 2003;Baxter et al, 2004;Murata et al, 2004;Ziegelbauer et al, 2005). PS1145 is one of these highly specific IKK inhibitors (ICo0.1 mM) recently developed by Millenium Pharmaceuticals, Inc. (Hideshima et al, 2002;Lam et al, 2005).…”

“…They include repression of NF-kB transactivation potential, stabilization of IkB inhibitors by proteasome inhibitors and, more recently, inhibition of upstream IKK kinases (Karin, 2004). The unique properties of IKKb among other serine-threonine kinases allowed successful development of specific IKKb inhibitors at Millennium Pharmaceuticals Inc. (Hideshima et al, 2002;Castro et al, 2003;Lam et al, 2005) and other companies (Burke et al, 2003;Kishore et al, 2003;Ziegelbauer et al, 2005). In the presented work, we studied the effect of the small-molecule IKK inhibitor PS1145 on the status of NF-kB in PC cells, PC cell growth, sensitivity of PC cells to apoptosis and on the invasion capability of PC cells.…”