IκB kinase β (IKKβ): Structure, transduction mechanism, biological function, and discovery of its inhibitors

Abstract

The effective approach to discover innovative drugs will ask natural products for answers because of their complex and changeable structures and multiple biological activities. Inhibitory kappa B kinase beta (IKKβ), known as IKK2, is a key regulatory kinase responsible for the activation of NF-κB through its phosphorylation at Ser177 and Ser181 to promote the phosphorylation of inhibitors of kappa B (IκBs), triggering their ubiquitination and degradation to active the nuclear factor kappa-B (NF-κB) cascade. Chemical inhibition of IKKβ or its genetic knockout has become an effective method to block NF-κB-mediated proliferation and migration of tumor cells and inflammatory response. In this review, we summarized the structural feature and transduction mechanism of IKKβ and the discovery of inhibitors from natural resources (e.g. sesquiterpenoids, diterpenoids, triterpenoids, flavonoids, and alkaloids) and chemical synthesis (e.g. pyrimidines, pyridines, pyrazines, quinoxalines, thiophenes, and thiazolidines). In addition, the biosynthetic pathway of novel natural IKKβ inhibitors and their biological potentials were discussed. This review will provide inspiration for the structural modification of IKKβ inhibitors based on the skeleton of natural products or chemical synthesis and further phytochemistry investigations.

Sesquiterpene Lactones Containing an α-Methylene-γ-Lactone Moiety Selectively Down-Regulate the Expression of Tumor Necrosis Factor Receptor 1 by Promoting Its Ectodomain Shedding in Human Lung Adenocarcinoma A549 Cells

“…Alantolactone was also shown to inhibit IκB kinase β by interacting with the ATP-binding site [29]. Since IκB kinase β plays an essential role in the NF-κB signaling pathway [24], IκB kinase β may be a common target protein of alantolactone in the NF-κB signaling pathway. In the present study, we found that TNF-R1 was down-regulated in A549 cells when they were exposed to alantolactone for 1 h. In contrast, alantolactone did not reduce the expression of TRADD, RIPK1, or TRAF2, which are adaptor proteins that are part of the TNF-R1 complex.…”

“…An α-methylene-γ-lactone moiety reacts with the thiol groups of proteins via the Michael addition reaction [22][23][24]. To clarify whether the α-methylene-γ-lactone moiety of alantolactone is critical for down-regulating the expression of TNF-R1, A549 cells were pretreated with glutathione, NAC, and L-cysteine, all of which contain a thiol group, and were then treated with alantolactone.…”

“…The biological activities of sesquiterpene lactones are mainly attributed to an α-methylene-γ-lactone moiety, which mainly reacts with the thiol groups of proteins [21]. Compounds with an α,β-unsaturated carbonyl moiety or α-methylene-γ-lactone moiety are known to form covalent bonds with the thiol groups of various proteins, including IκB kinases, in the NF-κB signaling pathway [22][23][24].…”

Connecting GSK-3β Inhibitory Activity with IKK-β or ROCK-1 Inhibition to Target Tau Aggregation and Neuroinflammation in Alzheimer’s Disease—Discovery, In Vitro and In Cellulo Activity of Thiazole-Based Inhibitors

“…pursuit of therapies for inflammatory, autoimmune, respiratory, and oncological conditions [40][41][42][43]. In an AD APP-transgenic murine model, IKKβ inhibition proved to be effective in reducing inflammatory microglial activation and decreasing TNF-α, Il-1β, and iNOS inflammatory gene transcription caused by Aβ deposits, thereby improving cognitive functions [44,45].…”

“…Subsequently, the released dimer translocates to the nucleus, where it regulates the gene expression of multiple inflammatory pathways [ 39 ]. The inhibition of IKKβ (also known as IKK2), with the aim of disrupting the activation of NF-κB, has garnered significant attention in the pursuit of therapies for inflammatory, autoimmune, respiratory, and oncological conditions [ 40 , 41 , 42 , 43 ]. In an AD APP-transgenic murine model, IKKβ inhibition proved to be effective in reducing inflammatory microglial activation and decreasing TNF-α, Il-1β, and iNOS inflammatory gene transcription caused by Aβ deposits, thereby improving cognitive functions [ 44 , 45 ].…”