Pharmacological inhibition of NF-κB-inducing kinase (NIK) with small molecules for the treatment of human diseases.

Abstract

NIK is a key kinase required for the activation of alternative NF-κB signaling pathways. Overactivation of NIK in patients has been observed and is implicated in the pathogenesis of inflammatory diseases, B-cell malignances, and solid tumors. Over the past decade, inhibition of NIK overactivation with small molecules has been pursued as an attractive strategy for drug discovery, where numerous potent and selective NIK inhibitors with novel pharmacophores have been identified. This review summarizes the structural features and key efficacy studies of the NIK inhibitors reported, which justify the mechanism of action of such inhibitors in animal models driven by NIK overactivation. Given the strong pathological associations between overactivation of NIK and human diseases, human clinical trials of NIK inhibitors as drug candidates are eagerly awaited. Information showcased in this review article might be helpful for the discovery and clinical development of the next generation of NIK inhibitors in the near future.