Abstract
Activation of IκB kinase β (IKK-β) and nuclear factor (NF)-κB signaling contributes to cancer pathogenesis and inflammatory disease; therefore, the IKK-β-NF-κB signaling pathway is a potential therapeutic target. Current drug design strategies focus on blocking NF-κB signaling by binding to specific cysteine residues on IKK-β. However, mutations in IKK-β have been found in patients who may eventually develop drug resistance. For these patients, a new generation of IKK-β inhibitors are required to provide novel treatment options. We demonstrate in vitro that cysteine-46 (Cys-46) is an essential residue for IKK-β kinase activity. We then validate the role of Cys-46 in the pathogenesis of inflammation using delayed-type hypersensitivity (DTH) and an IKK-β C46A transgenic mouse model. We show that a novel IKK-β inhibitor, dihydromyricetin (DMY), has anti-inflammatory effects on WT DTH mice but not IKK-β C46A transgenic mice. These findings reveal the role of Cys-46 in the promotion of inflammatory responses, and suggest that Cys-46 is a novel drug-binding site for the inhibition of IKK-β.
Highlights
Disease pathogenesis, drug response, drug resistance, and drug toxicity are all correlated with the genetic background of individual patients [1,2,3]; personalized therapies targeting specific genes or gene mutations are highly desirable [4, 5]
We further showed that delayed-type hypersensitivity (DTH) in the homozygous IKK-βC46A mutant mice resulted in severe inflammation and diminished the antiinflammatory effects of dihydromyricetin (DMY), a novel IKK-β inhibitor derived from the medicinal plant Ampelopsis megalophylla
Using site-directed mutagenesis, we found that mutation of IKK-β cysteine-46 to alanine (C46A) increased kinase activity in vitro (Figure 1A)
Summary
Drug response, drug resistance, and drug toxicity are all correlated with the genetic background of individual patients [1,2,3]; personalized therapies targeting specific genes or gene mutations are highly desirable [4, 5]. Each drugs’ inhibitory activity varies depending on its binding affinity to specific functional sites on IKK-β, including the cysteine (Cys)-179 residue, the ATP binding domain, the allosteric domain, and serine (Ser)-177/-181 residues [12, 14, 15, 20, 21]. Many of these sites, or other unidentified sites are variants in patients [7, 22,23,24,25], altering the effects of these drugs. As cysteine residues participate in the catalysis and activation of IKK-β [26,27,28], the identification and characterization of cysteine mutations in IKK-β is essential to unravel the pathogenesis of IKK-β-related diseases and broaden the spectrum of novel IKK-β-based drug design [29,30,31,32]
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