Abstract
Deregulated NF-κB signalling is implicated in the pathogenesis of numerous human inflammatory disorders and malignancies. Consequently, the NF-κB pathway has attracted attention as an attractive therapeutic target for drug discovery. As the primary, druggable mediator of canonical NF-κB signalling the IKKβ protein kinase has been the historical focus of drug development pipelines. Thousands of compounds with activity against IKKβ have been characterised, with many demonstrating promising efficacy in pre-clinical models of cancer and inflammatory disease. However, severe on-target toxicities and other safety concerns associated with systemic IKKβ inhibition have thus far prevented the clinical approval of any IKKβ inhibitors. This review will discuss the potential reasons for the lack of clinical success of IKKβ inhibitors to date, the challenges associated with their therapeutic use, realistic opportunities for their future utilisation, and the alternative strategies to inhibit NF-κB signalling that may overcome some of the limitations associated with IKKβ inhibition.
Highlights
There are five members of the nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells (NF-κB) transcription factor family in mammals: RelA (p65), RelB, c-Rel, NF-κB1 (p50, initially synthesised as a larger precursor, p105) and NF-κB2 (p52, initially synthesised as a larger precursor, p100)
Polley et al demonstrated that the introduction of mutations within the two oligomerization interfaces identified in their constitutively active (S177E/S181E) human IKKβ X-ray crystal structure—the scaffold/dimerization domain (SDD)-SDD interface of dimeric IKKβ (Figure 3B,C), and the kinase domain (KD)-KD interface of oligomeric IKKβ (Figure 3D,E)—was sufficient to interfere with IKKβ activation/catalytic activity in vitro, indicating that small molecules designed to interfere with IKKβ oligomerization through these interfaces may function as highly selective inhibitors of Another reason for the lack of success of IKKβ inhibitors in pre-clinical development may be their inappropriate therapeutic application
The former strategy has been demonstrated in pre-clinical studies investigating the use of IKKβ inhibitors to treat choroid neovascularization (CNV), which is a major pathological change associated with exudative age-related macular degeneration (AMD) [223]
Summary
There are five members of the nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells (NF-κB) transcription factor family in mammals: RelA (p65), RelB, c-Rel, NF-κB1 (p50, initially synthesised as a larger precursor, p105) and NF-κB2 (p52, initially synthesised as a larger precursor, p100). All members share a conserved Rel homology domain (RHD) that enables them to associate with each other to form a diverse array of transcriptionally active homo- and hetero-dimeric complexes. The transcriptional activity of NF-κB dimers is regulated by several distinct pathways (Figure 1). Engagement of the canonical NF-κB pathways triggers signalling cascades that converge on activation of the IκB kinase (IKK) complex, which is formed by the kinase subunits, IKKα and IKKβ, and a regulatory subunit, IKKγ Several atypical pathways are capable of activating activating theinIKK complex in response to diverse as DNA damage These distinct NF-κB pathways regulate different subsets of target genes, and different.
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