A novel allosteric inhibitor that prevents IKKβ activation.

ABSTRACT: I kappa B kinase β (IKKβ) is one of the primary targets to regulate canonical NF-κB activity. The misregulation of NF-κB is associated with various diseases, including chronic inflammation and cancers. Most of the known IKKβ inhibitors target its active form and suffer from poor selectivity. In the present study, we aim to design inhibitors that can bind to the IKKβ inactive form and block its activation. We identified a potential allosteric site between the kinase domain (KD) and ubiquitin-like domain (ULD) of human IKKβ and used it to virtually screen a chemical library for allosteric inhibitors. Among the 133 compounds tested, 16 inhibited NF-κB activity by over 50% at 50 μM in a reporter gene assay. Further quantitative measurements and cytotoxicity study gave one compound 124 (

SUBMITTER: Liu H 

PROVIDER: S-EPMC6083782 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature