The discovery of 2-amino-3,5-diarylbenzamide inhibitors of IKK-α and IKK-β kinases

Christopher, John; Avitabile, Barbara G.; Bamborough, Paul; Champigny, Aurélie C.; Cutler, Geoffrey J.; Dyos, Susan L.; Grace, Ken; Kerns, Jeffrey K.; Kitson, Jeremy; Mellor, Geoffrey W.; Morey, J. V.; Morse, Mary A.; O’Malley, Carolyn F.; Patel, Champa; Probst, Nicholas; Rumsey, William L.; Smith, Clive A.; Wilson, Michael J.

doi:10.1016/j.bmcl.2007.04.088

Cited by 59 publications

(38 citation statements)

References 12 publications

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“…Interestingly, IKK Inhibitor XII, a selective inhibitor of NF- к B signalling that functions by decreasing NF- к B phosphorylation and thus reducing the probability of translocation of the NF- к B into the nucleus, also prevented SAPK/JNK activation in LPS-treated cells (Figure 2). These results coincide with findings demonstrating that SAPK/JNK signalling is regulated by the NF- к B pathway [20, 21]. Indeed, it is generally suggested that NF- к B activation plays a critical role in LPS-induced responses and that the suppression of NF- к B pathway activity prevents its ability to activate the transcription of a wide variety of genes encoding immunologically relevant proteins.…”

Section: Discussionsupporting

confidence: 89%

Anti-Inflammatory Effects of IKK Inhibitor XII, Thymulin, and Fat-Soluble Antioxidants in LPS-Treated Mice

Новоселова

Хренов

Глушкова

et al. 2014

Mediators of Inflammation

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The present study was designed to compare the anti-inflammatory effects of several agents applied in vivo, namely, a synthetic inhibitor of the NF-κB cascade, fat-soluble antioxidants, and the thymic peptide thymulin. Cytokine response in LPS-treated mice was analysed in tandem with the following parameters: the synthesis of inducible forms of the heat shock proteins HSP72 and HSP90α; activity of the NF-κB and SAPK/JNK signalling pathways; and TLR4 expression. Inflammation-bearing Balb/c male mice were pretreated with an inhibitor of IKK-α/β kinases (IKK Inhibitor XII); with thymulin; with dietary coenzyme Q9, α-tocopherol, and β-carotene; or with combinations of the inhibitor and peptide or antioxidants. Comparable anti-inflammatory effects were observed in inflammation-bearing mice treated separately with thymulin or with dietary antioxidants administered daily for two weeks before LPS treatment. When LPS-injected mice were treated with the inhibitor and antioxidants together, neither plasma cytokines, signal proteins, nor heat shock proteins recovered more efficiently than when mice were treated with these agents separately. In contrast to antioxidant diet, the thymulin was shown to increase the effect of IKK Inhibitor XII in preventing IKK activation in LPS-treated mice.

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Section: Discussionsupporting

confidence: 89%

Anti-Inflammatory Effects of IKK Inhibitor XII, Thymulin, and Fat-Soluble Antioxidants in LPS-Treated Mice

Новоселова

Хренов

Глушкова

et al. 2014

Mediators of Inflammation

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“…41,42 The phase I clinical trial of topical formulation of IMD-0354 for treatment of atopic dermatitis has been successfully completed. Other synthetic IKK inhibitors, including S1627, 43 2-benzamido-pyrimidines, 44 2-amino-3,5-diarylbenzamides, 45,46 6-aryl-7-alkoxyisoquinolines, 47 4-phenyl-7-azaindoles, 48 PHA-408 49,50 and PF-184, 50 have been reported.…”

Section: Synthetic Ikk Inhibitorsmentioning

confidence: 99%

Chemical biology of inflammatory cytokine signaling

Kataoka

2009

J Antibiot

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Pro-inflammatory cytokines, such as tumor necrosis factor-a and interleukin-1, trigger the signal transduction pathway leading to the activation of the transcription factor, nuclear factor-jB (NF-jB). NF-jB induces a large number of target genes involved in many biological processes, such as inflammation, immunity, cell survival, cell death and carcinogenesis. As therapeutic agents for inflammatory diseases and cancer, as well as bioprobes for the characterization of intracellular biological response and cell function, a large number of natural and synthetic small molecules have been identified to inhibit the activation of the NF-jB signaling pathway. This review focuses on recent progress in the identification and biological properties of small molecules targeting the NF-jB signaling pathway induced by pro-inflammatory cytokines.

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“…According to previous studies [12,14,38,39] those models representing portions of the enzyme far from the active site (the ATP binding pocket comprised between residues 44, 90, and 145) were discarded. The resulting models were further discriminated by examining the percentage of identity with the template sequence and the provided ModelScore value.…”

Section: Resultsmentioning

confidence: 99%

“…SAR modifications on this compound allowed the design of 2-(aminocarbonyl)amino-5-acetylenyl-3-thiophenecarboxamides (2) [13], a novel class of inhibitors with an improved activity and selectivity. More recently [14], the IKK-␤ inhibitors providing a 2-amino-3,5-diarylbenzamide scaffold (3) were discovered starting from structure-activity studies on a series of IKK-inhibitors, part of an PMA-inducible IkB kinase complex with a structural homology to IKK-␣ of 30% [15].…”

Section: Introductionmentioning

confidence: 99%

IKK-β inhibitors: An analysis of drug–receptor interaction by using Molecular Docking and Pharmacophore 3D-QSAR approaches

Lauria

Ippolito

Fazzari

et al. 2010

Journal of Molecular Graphics and Modelling

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The discovery of 2-amino-3,5-diarylbenzamide inhibitors of IKK-α and IKK-β kinases

Cited by 59 publications

References 12 publications

Anti-Inflammatory Effects of IKK Inhibitor XII, Thymulin, and Fat-Soluble Antioxidants in LPS-Treated Mice

Anti-Inflammatory Effects of IKK Inhibitor XII, Thymulin, and Fat-Soluble Antioxidants in LPS-Treated Mice

Chemical biology of inflammatory cytokine signaling

IKK-β inhibitors: An analysis of drug–receptor interaction by using Molecular Docking and Pharmacophore 3D-QSAR approaches

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