Various inflammatory stimuli that activate the nuclear factor kappa B (NF-κB) signaling pathway converge on a serine/threonine kinase that displays a key role in the activation of NF-κB: the I kappa B kinase β (IKK-β). Therefore, IKK-β is considered an interesting target for combating inflammation and cancer. In our study, we developed a ligand-based pharmacophore model for IKK-β inhibitors. This model was employed to virtually screen commercial databases, giving a focused hit list of candidates. Subsequently, we scored by molecular shape to rank and further prioritized virtual hits by three-dimensional shape-based alignment. One out of ten acquired and biologically tested compounds showed inhibitory activity in the low micromolar range on IKK-β enzymatic activity in vitro and on NF-κB transactivation in intact cells. Compound 8 (2-(1-adamantyl)ethyl 4-[(2,5-dihydroxyphenyl)methylamino]benzoate) represents a novel chemical class of IKK-β inhibitors and shows that the presented model is a valid approach for identification and development of new IKK-β ligands. © 2010 Elsevier Ltd. All rights reserved.
Noha, S. M., Atanasov, A. G., Schuster, D., Markt, P., Fakhrudin, N., Heiss, E. H., … Wolber, G. (2011). Discovery of a novel IKK-β inhibitor by ligand-based virtual screening techniques. Bioorganic and Medicinal Chemistry Letters, 21(1), 577–583. https://doi.org/10.1016/j.bmcl.2010.10.051