Inhibitor of nuclear factor kappa-B kinase subunit epsilon and TANK-binding kinase 1 protein-protein interface (IKKε–TBK1 PPI)

The Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKε) and TANK-binding kinase 1 (TBK1) protein-protein interface is a critical structural target involved in the regulation of innate immunity and cell survival. These two non-canonical IKK kinases share high homology and function as dimers, with their interface—primarily located in the scaffold/dimerization domain (SDD)—being essential for their activation and recruitment to signaling adapters like TANK, NAP1, and SINTBAD (Ma et al., 2012; Goncalves et al., 2011). This interface facilitates the assembly of complexes that activate Interferon Regulatory Factors (IRF3/7) and NF-κB, driving the production of Type I interferons and pro-survival signals. In oncogenesis, the IKKε–TBK1 interface is often exploited to promote immune evasion and resistance to apoptosis, specifically by phosphorylating RIPK1 at the TNFR1 complex to prevent cell death (Cell Death Discov, 2025). Therapeutic targeting of this interface, using novel disruptors like idronoxil or dual inhibitors like amlexanox, aims to block these interactions to treat cancer, autoimmune diseases, and hyperinflammatory conditions like COVID-19 (Ullah et al., 2023). Pharmacological intervention at this interface poses challenges, including the risk of systemic immunosuppression and the potential for exacerbating certain inflammatory responses by disinhibiting the NLRP3 inflammasome (Ullah et al., 2023). Overall, the IKKε–TBK1 interface represents a sophisticated target for modulating the balance between immune activation and cell death in various disease states.

Other names

IKBKE-TBK1 interfaceNon-canonical IKK interfaceTBK1-IKKε dimerization interfaceIKKε-TBK1-adapter interfaceIKK-related kinase interface

Inhibition of protein-protein interaction to prevent kinase dimerization and recruitment to signaling adapters or complexes, thereby blocking downstream IRF3 and NF-κB signaling.