Inhibition of I?B kinase-? and I?B kinase-? by heterocyclic adamantyl arotinoids.

ABSTRACT: We recently reported on a series of retinoid-related molecules containing an adamantyl group, a.k.a. adamantyl arotinoids (AdArs), that showed significant cancer cell growth inhibitory activity and activated RXR? (NR2B1) in transient transfection assays while devoid of RAR transactivation capacity. We have now explored whether these AdArs could also bind and inhibit IKK?, a known target that mediates the induction of apoptosis and cancer cell growth inhibition by related AdArs containing a chalcone functional group. In addition, we have prepared and evaluated novel AdArs that incorporate a central heterocyclic ring connecting the adamantyl-phenol and the carboxylic acid at the polar termini. Our results indicate that the majority of the RXR? activating compounds lacked IKK? inhibitory activity. In contrast, the novel heterocyclic AdArs containing a thiazole or pyrazine ring linked to a benzoic acid motif were potent inhibitors of both IKK? and IKK?, which in most cases paralleled significant growth inhibitory and apoptosis inducing activities.

SUBMITTER: Garcia-Rodriguez J 

PROVIDER: S-EPMC6805150 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature