Adamantyl Arotinoids That Inhibit IB Kinase and IB Kinase

A series of analogues of the adamantyl arotinoid (AdAr) chalcone MX781 with halogenated benzyloxy substituents at C2 and heterocyclic derivatives replacing the chalcone group were found to inhibit IB kinase (IKK) and IB kinase (IKK) activities. The growth inhibitory capacity of some analogues against Jurkat Tcells as well as prostate carcinoma (PC-3) and chronic myelogenous leukemia (K562) cells, which contain elevated basal IKK activity, correlates with the induction of apoptosis and increased inhibition of recombinant IKK and IKK invitro, pointing toward inhibition of IKK/NFB signaling as the most likely target of the anticancer activities of these AdArs. While the chalcone functional group present in many dietary compounds has been shown to mediate interactions with IKK via Michael addition with cysteine residues, AdArs containing a five-membered heterocyclic ring (isoxazoles and pyrazoles) in place of the chalcone of the parent system are potent inhibitors of IKKs as well, which suggests that other mechanisms for inhibition exist that do not depend on the presence of a reactive ,-unsaturated ketone.