A novel, highly selective, tight binding IκB kinase-2 (IKK-2) inhibitor: A tool to correlate IKK-2 activity to the fate and functions of the components of the nuclear factor-κb pathway in arthritis-relevant cells and animal models

Gabriel Mbalaviele, Cynthia D. Sommers, Sheri L. Bonar, Sumathy Mathialagan, John F. Schindler, Julia A. Guzova, Alexander F. Shaffer, Michele A. Melton, Lori J. Christine, Catherine S. Tripp, Po Chang Chiang, David C. Thompson, Yiding Hu, Nandini Kishore

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51 Scopus citations

Abstract

Nuclear factor (NF)-κB activation has been clearly linked to the pathogenesis of multiple inflammatory diseases including arthritis. The central role that IκB kinase-2 (IKK-2) plays in regulating NF-κB signaling in response to inflammatory stimuli has made this enzyme an attractive target for therapeutic intervention. Although diverse chemical classes of IKK-2 inhibitors have been identified, the binding kinetics of these inhibitors has limited the scope of their applications. In addition, safety assessments of IKK-2 inhibitors based on a comprehensive understanding of the pharmacokinetic/pharmacodynamic relationships have yet to be reported. Here, we describe a novel, potent, and highly selective IKK-2 inhibitor, PHA-408 [8-(5-chloro-2-(4-meth-ylpiperazin-1-yl)isonicotinamido)-1-(4-fluorophenyl)-4, 5-dihydro1H-benzo[g]indazole-3-carboxamide]. pHa-408 is an ATP competitive inhibitor, which binds IKK-2 tightly with a relatively slow off rate. In arthritis-relevant cells and animal models, PHA408 suppresses inflammation-induced cellular events, including Iκalpha; phosphorylation and degradation, p65 phosphorylation and DNA binding activity, the expression of inflammatory mediators, and joint pathology. PHA-408 was efficacious in a chronic model of arthritis with no adverse effects at maximally efficacious doses. Stemming from its ability to bind tightly to IKK-2, as a novelty, we demonstrated that PHA-408-mediated inhibition of IKK-2 activity correlated very well with its ability to modulate the fate of IKK-2 substrates and downstream transcriptional events. We ultimately directly linked IKK-2 activity ex vivo and in vivo to markers of inflammation with the inhibitor plasma concentrations. Thus, PHA-408 represents a powerful tool to further gain insight into the mechanisms by which IKK-2 regulates NF-slow off rate. In arthritis-relevant cells and animal models, PHA408 suppresses inflammation-induced cellular events, including IκBalpha; phosphorylation and degradation, p65 phosphorylation and DNA binding activity, the expression of inflammatory mediators, and joint pathology. PHA-408 was efficacious in a chronic model of arthritis with no adverse effects at maximally efficacious doses. Stemming from its ability to bind tightly to IKK-2, as a novelty, we demonstrated that PHA-408-mediated inhibition of IKK-2 activity correlated very well with its ability to modulate the fate of IKK-2 substrates and downstream transcriptional events. We ultimately directly linked IKK-2 activity ex vivo and in vivo to markers of inflammation with the inhibitor plasma concentrations. Thus, PHA-408 represents a powerful tool to further gain insight into the mechanisms by which IKK-2 regulates NF-slow off rate. In arthritis-relevant cells and animal models, PHA408 suppresses inflammation-induced cellular events, including IκBalpha; phosphorylation and degradation, p65 phosphorylation and DNA binding activity, the expression of inflammatory mediators, and joint pathology. PHA-408 was efficacious in a chronic model of arthritis with no adverse effects at maximally efficacious doses. Stemming from its ability to bind tightly to IKK-2, as a novelty, we demonstrated that PHA-408-mediated inhibition of IKK-2 activity correlated very well with its ability to modulate the fate of IKK-2 substrates and downstream transcriptional events. We ultimately directly linked IKK-2 activity ex vivo and in vivo to markers of inflammation with the inhibitor plasma concentrations. Thus, PHA-408 represents a powerful tool to further gain insight into the mechanisms by which IKK-2 regulates NF-κB signaling and validates IKK-2 as a therapeutic target. signaling and validates IKK-2 as a therapeutic target. signaling and validates IKK-2 as a therapeutic target.

Original languageEnglish
Pages (from-to)14-25
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume329
Issue number1
DOIs
StatePublished - Apr 1 2009
Externally publishedYes

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    Mbalaviele, G., Sommers, C. D., Bonar, S. L., Mathialagan, S., Schindler, J. F., Guzova, J. A., Shaffer, A. F., Melton, M. A., Christine, L. J., Tripp, C. S., Chiang, P. C., Thompson, D. C., Hu, Y., & Kishore, N. (2009). A novel, highly selective, tight binding IκB kinase-2 (IKK-2) inhibitor: A tool to correlate IKK-2 activity to the fate and functions of the components of the nuclear factor-κb pathway in arthritis-relevant cells and animal models. Journal of Pharmacology and Experimental Therapeutics, 329(1), 14-25. https://doi.org/10.1124/jpet.108.143800