Design, synthesis, and biological evaluation of novel NIK inhibitors for the treatment of inflammatory bowel disease and sepsis

NF-κB-inducing kinase (NIK) plays a pivotal role in activating the non-canonical NF-κB pathway, and its dysregulation has been strongly implicated in autoimmune and inflammatory diseases. In this study, we conducted a structure-based drug design campaign starting from lead compound 5 and successfully identified compound 38 as a novel, highly potent NIK inhibitor, exhibiting an IC₅₀ of 5.2 ± 2.8 nM. Compound 38 demonstrated pronounced anti-inflammatory effects in vitro, including suppression of Th17 cell differentiation and inhibition of proinflammatory cytokine production in macrophages. It also displayed favorable pharmacokinetic properties, with 45 % oral bioavailability in mice. In vivo, compound 38 showed marked therapeutic efficacy in a DSS-induced colitis model, comparable to that of 5-aminosalicylic acid, and significantly improved survival and attenuated liver injury in an LPS-induced sepsis model. Collectively, these findings establish compound 38 as a promising preclinical candidate for the treatment of inflammatory bowel disease (IBD) and sepsis, and further validate NIK as a compelling therapeutic target.