NF-κB inducing kinase (NIK) is a key regulator in the noncanonical nuclear factor κB cells (NF-κB) signaling pathway. Dysregulation of NIK is often related with autoimmune disorders and malignancies. However, the number of reported NIK inhibitors is scarce. Discriminatory analysis-based molecular docking was used to examine the accuracy of the binding conformation and to estimate the binding affinity, leading to the identification of several new NIK inhibitors with moderate IC50 (ranging from 48.9 to 103.4 μM). Among them, compound 5, the most potent one (IC50 48.9 ± 6.9 μM), also showed moderate antiproliferation activity against cancer SW1990 cells, with an IC50 value of 20.1 ± 6.0 μM. Further dynamic simulations were performed to provide more in-depth details on the binding conformation of compound 5 and the NIK protein, providing some structural clues for further optimization of compound 5 as a novel NIK inhibitor.
Keywords: NF-κB inducing kinase; antiproliferation activity; inhibitors; virtual screen.
© 2019 Deutsche Pharmazeutische Gesellschaft.