sc-514 and Edema

In this study, we describe the rational design, molecular modeling and pharmacological profile of a novel IKK-β inhibitor (E)-N-(4-nitrobenzylidene)-2-naphthohydrazide (LASSBio-1524). The design based on the IKK-β active site, and a privileged structure template yielded a novel IKK-β inhibitor scaffold with significant selectivity over IKK-α and CHK2, as assessed by an in vitro kinase assay. For a better understanding of the structural requirements of IKK-β inhibition, molecular dynamics simulations of LASSBio-1524 (3) were performed. The NAH derivative LASSBio-1524 (3), was able to suppress arachidonic acid-induced edema formation in a dose-dependent manner, demonstrating an in vivo anti-inflammatory effect. The molecular architecture of this novel, low-molecular weight IKK-β inhibitor is encouraging for further lead optimization toward the development of innovative anti-inflammatory drug candidates.

Topics: Amino Acid Sequence; Animals; Anti-Inflammatory Agents; Benzylidene Compounds; Catalytic Domain; Cell Line; Drug Design; Edema; Female; Humans; Hydrazones; I-kappa B Kinase; Ligands; Male; Mice; Molecular Dynamics Simulation; Molecular Sequence Data; Molecular Weight; Protein Kinase Inhibitors