Gibberellin JRA-003: A Selective Inhibitor of Nuclear Translocation of IKKα

The
small molecule gibberellin JRA-003 was identified as an inhibitor
of the NF-kB (nuclear kappa-light-chain-enhancer of activated B cells)
pathway. Here we find that JRA-003 binds to and significantly inhibits
the nuclear translocation of pathway-activating kinases IKKα
(IκB kinase alpha) and IKKβ (IκB kinase beta). Analogs
of JRA-003 were synthesized and NF-κB-inhibiting gibberellins
were found to be cytotoxic in cancer-derived cell lines (HS 578T,
HCC 1599, RC-K8, Sud-HL4, CA 46, and NCIH 4466). Not only was JRA-003
identified as the most potent synthetic gibberellin against cancer-derived
cell lines, it displayed no cytotoxicity in cells derived from noncancerous
sources (HEK 293T, HS 578BST, HS 888Lu, HS 895Sk, HUVEC). This selectivity
suggests a promising approach for the development of new therapeutics.