Discovery of a novel IKK-beta inhibitor by ligand-based virtual screening techniques

Various inflammatory stimuli that activate the nuclear factor kappa B (NF-kappa B) signaling pathway converge on a serine/threonine kinase that displays a key role in the activation of NF-kappa B: the I kappa beta Bkinase beta (IKK-beta). Therefore, IKK-beta is considered an interesting target for combating inflammation and cancer. In our study, we developed a ligand-based pharmacophore model for IKK-beta 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-beta enzymatic activity in vitro and on NF-kappa B transactivation in intact cells. Compound 8 (2-(1-adamantyl) ethyl 4-[(2,5-dihydroxyphenyl) methylamino] benzoate) represents a novel chemical class of IKK-beta inhibitors and shows that the presented model is a valid approach for identification and development of new IKK-beta ligands. (C) 2010 Elsevier Ltd. All rights reserved.