Studies on gambogic acid (IV): Exploring structure–activity relationship with IκB kinase-beta (IKKβ)

Previously we have reported a series of gambogic acid's analogs and have identified a compound that possessed comparable in vitro growth inhibitory effect as gambogic acid. However, their target protein as well as the key pharmacophoric motifs on the target have not been identified yet. Herein we report that gambogic acid and its analogs inhibit the activity of IκB Kinase-beta (IKKβ) through suppressing the activation of TNFα/NF-κB pathway, which in turn induces A549 and U251 cell apoptosis. IKKβ can serve as one of gambogic acid's targets. The preparation of the compounds was carefully discussed in the article. Caged 4-oxa-tricyclo[4.3.1.03,7]dec-2-one xanthone, which was identified as the pharmacophoric scaffold, represents a promising therapeutic agent for cancer and useful probe against NF-κB pathway.

Graphical AbstractIKKβ was identified as the molecular target of GA through the research of NF-κB signaling pathway. A series of GA's analogs were synthesized to identify the pharmacophoric motifs against IKKβ.Figure optionsDownload as PowerPoint slideHighlights
► IKKβ was identified as the key molecular target of gambogic acid (GA).
► Caged 4-oxa-tricyclo[4.3.1.03,7]dec-2-one xanthone was a new scaffold of IKKβ inhibitor.
► Ten simplified GA derivatives were designed and synthesized.
► Compound 20 has equal activity and similar mechanism with GA.
► The binding modes of 4 compounds with IKKβ were studied by molecular modeling.